Clinical Cancer Research最新文献

{"title":"Follow-Up Analysis Enhances Understanding of Molecular Residual Disease in Localized Non-Small Cell Lung Cancer","authors":"Jia-Tao Zhang, Si-Yang Liu, Xuan Gao, Si-Yang Maggie. Liu, Bingfa Yan, Chen Huang, Zicong Jiao, Hong-Hong Yan, Yi Pan, Song Dong, Wei Gao, Yuhua Gong, Hai-Yan Tu, Xue-Feng Xia, Qing Zhou, Wen-Zhao Zhong, Xue-Ning Yang, Xin Yi, Yi-Long Wu","doi":"10.1158/1078-0432.ccr-24-2909","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-2909","url":null,"abstract":"Purpose: The prognostic value of molecular residual disease (MRD) in non-small cell lung cancer (NSCLC) is well-established, with treatment-guiding results anticipated. Here, we present updated analyses from our previous published cohort study of 261 NSCLC patients undergoing complete resection. Experimental Design: 261 patients with stage I-III lung cancer who underwent radical surgery were enrolled. Enrolled patients underwent follow-up blood draws according to the predefined time points after surgery. As of December 31st, 2023, with a median follow-up of 43.4 months, 948 postoperative blood samples were collected. Results: Landmark and longitudinal MRD exhibited positive predictive values of 91.3% and 92.8%, respectively, with a median lead times of 5.2 months. Negative predictive values were 76.5% and 93.2%, respectively. Patients with landmark undetectable MRD could not be benefited from adjuvant therapy through the updated follow-up (p=0.529). Among the 13 patients with recurrent NSCLC and longitudinal undetectable MRD, seven (53.8%) had brain-only metastases, and four (30.8%) had no updated blood samples for over six months prior to recurrence. Besides, for those with longitudinal detectable MRD, higher maximum variant allele frequency (>0.55%) and ctDNA level (>13 hGE/ml) were associated with a high risk of short-term recurrence. Additionally, updated follow-up data further support the peak time for detectable MRD was 18 months after landmark detection. Conclusions: These findings suggest the significant potential of MRD in guiding personalized treatment for NSCLC. And postoperative longitudinal undetectable MRD can indicate a cured population.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"58 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143030988","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Vvax001, a Therapeutic Vaccine for Patients with HPV16-positive High-grade Cervical Intraepithelial Neoplasia: a Phase II Trial","authors":"Anneke L. Eerkens, Martha D. Esajas, Koen Brummel, Annegé Vledder, Nienke van Rooij, Annechien Plat, Stefany B. Avalos Haro, Sterre T. Paijens, Lorian Slagter-Menkema, Ed Schuuring, Naomi Werner, Jos G.W. Kosterink, Bart-Jan Kroesen, Jan C. Wilschut, Toos Daemen, Joost Bart, Hans W. Nijman, Marco de Bruyn, Refika Yigit","doi":"10.1158/1078-0432.ccr-24-1662","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-1662","url":null,"abstract":"Purpose: Human papillomavirus (HPV) infection is the major cause of (pre)malignant cervical lesions. We previously demonstrated that Vvax001, a replication-incompetent Semliki Forest virus (SFV) vaccine encoding HPV type 16 (HPV16) E6 and E7, induced potent anti-E6 and -E7 cytotoxic T-cell responses. Here, we investigated the clinical efficacy of Vvax001 in patients with HPV16-positive cervical intraepithelial neoplasia grade 3 (CIN3). Patients and Methods: Patients with newly diagnosed HPV16-positive CIN3 were eligible for participation. Patients received 3 immunizations of Vvax001 (5x107 infectious particles) at a three-week interval. Up to 19 weeks after the last immunization patients were monitored for regression of CIN3 by colposcopy. A colposcopy-guided biopsy was taken at the last visit and a standard of care loop excision was performed only in case of remaining CIN2/3. Histopathologic response rates, HPV16 clearance, treatment-related adverse events (trAEs), and vaccine-induced immune responses were assessed. Results: A total of 18 patients were enrolled and fully immunized. Colposcopic examination revealed a reduction in CIN3 lesion sizes in 17/18 patients (94%) already evident from 3 weeks onwards after the last immunization. A histopathological complete response (regression to CIN1 or no dysplasia) was observed in 9/18 patients (50%), and HPV16 clearance in 10/16 patients (63%). Vvax001 did not induce clearance of other HPV types. To date, no recurrences have been observed, with a median and longest disease-free survival of 20 and 30 months, respectively. No serious AEs were observed. Conclusions: Treatment with Vvax001 is safe, feasible, and shows preliminary clinical effectiveness in patients with HPV16-associated CIN3 lesions.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"2 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143027223","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intratumoral or Subcutaneous MK-2118, a Non-Cyclic Dinucleotide STING Agonist, With or Without Pembrolizumab for Advanced or Metastatic Solid Tumors or Lymphomas.","authors":"Jason J Luke, Randy F Sweis, J Randolph Hecht, Reva Schneider, Mark N Stein, Talia Golan, Timothy A Yap, Anuradha Khilnani, Mo Huang, Runchen Zhao, Thomas Jemielita, Sandip Pravin Patel","doi":"10.1158/1078-0432.CCR-24-2824","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-2824","url":null,"abstract":"<p><strong>Background: </strong>We evaluated the non-cyclic dinucleotide stimulator of interferon genes agonist MK-2118 ± pembrolizumab in patients with advanced solid tumors or lymphomas.</p><p><strong>Methods: </strong>This first-in-human study (NCT03249792) enrolled patients with refractory, advanced solid tumors or lymphomas. Patients received intratumoral (IT) MK-2118 100-20,000 µg (arm 1), IT MK-2118 900-15,000 µg plus intravenous (IV) pembrolizumab 200 mg every 3 weeks (Q3W; arm 2), or subcutaneous (SC) MK-2118 5000-150,000 µg plus IV pembrolizumab 200 mg Q3W (arm 4); arm 3 (visceral injection of MK-2118) was not pursued. IT dosing used an accelerated titration design and modified toxicity probability interval method; SC dosing (arm 4) was started subsequent to arms 1 and 2. Primary objectives were safety/tolerability. MK-2118 pharmacokinetics were a secondary endpoint; objective responses and biomarkers were exploratory endpoints.</p><p><strong>Results: </strong>140 patients were enrolled (arm 1, n=27; arm 2, n=57; arm 4, n=56). Grade 3/4 treatment-related adverse events occurred in 22%, 23%, and 11% of patients, respectively, but no maximum tolerated dose was identified up to MK-2118 20,000, 15,000, and 150,000 µg across the 3 arms. Dose-dependent increases in MK-2118 systemic exposure were observed following IT and SC administration. Objective responses were seen in 0%, 6%, and 4% of patients, respectively. IT MK-2118 led to dose-dependent changes in STING-based blood RNA expression levels, interferon-gamma, interferon-gamma‒induced protein 10, and interleukin-6; SC MK-2118 did not generate dose-related immune responses.</p><p><strong>Conclusion: </strong>IT MK-2118 ± pembrolizumab and SC MK-2118 plus pembrolizumab had manageable toxicity and limited antitumor activity. IT but not SC administration demonstrated systemic immune effects.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143022360","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"First-in-Human Phase 1 study of a CD16A bispecific innate cell engager, AFM24, targeting EGFR-expressing solid tumors.","authors":"Anthony El-Khoueiry, Omar Saavedra, Jacob Thomas, Claire Livings, Elena Garralda, Gabriele Hintzen, Laura Kohlhas, Dessislava Vanosmael, Joachim Koch, Erich Rajkovic, Paulien Ravenstijn, Paolo Nuciforo, Todd A Fehniger, Mark Foster, Melissa M Berrien-Elliott, Susanne Wingert, Sina Stäble, Daniela Morales-Espinosa, Delcia Rivas, Michael Emig, Juanita Lopez","doi":"10.1158/1078-0432.CCR-24-1991","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-1991","url":null,"abstract":"<p><strong>Purpose: </strong>Innate immune cell-based therapies have shown promising antitumor activity against solid and hematologic malignancies. AFM24, a bispecific innate cell engager, binds CD16A on natural killer (NK) cells/macrophages and EGFR on tumor cells, redirecting antitumor activity towards tumors. The safety and tolerability of AFM24 was evaluated in this Phase 1/2a dose escalation/dose expansion study in patients with recurrent or persistent, advanced solid tumors known to express EGFR.</p><p><strong>Methods: </strong>The main objective in Phase 1 was to determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D). The primary endpoint was the incidence of dose-limiting toxicities (DLTs) during the observation period. Secondary endpoints included the incidence of treatment emergent adverse events and pharmacokinetics.</p><p><strong>Results: </strong>In the dose escalation phase, 35 patients received AFM24 weekly across seven dose cohorts (14-720 mg). One patient experienced a DLT of Grade 3 infusion-related reaction (IRR). IRRs were mainly reported after the first infusion; these were manageable with premedication and a gradual increase in infusion rate. Pharmacokinetics were dose-proportional and CD16A receptor occupancy on NK cells approached saturation between 320-480 mg. Paired tumor biopsies demonstrated activation of innate and adaptive immune responses within the tumor. Best objective response was stable disease in 10/35 patients; four had stable disease for 4.3-7.1 months.</p><p><strong>Conclusions: </strong>AFM24 was well tolerated with 480 mg established as the RP2D. AFM24 could be a novel therapy for patients with EGFR-expressing solid tumors with suitable tolerability and appropriate pharmacokinetic properties for further development in combination with other immuno-oncology therapeutics.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143022357","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Human Epidermal Growth Factor Receptor 2 Loss Following Treatment with Trastuzumab Deruxtecan in Patients with Metastatic Breast Cancer","authors":"Mohamed A. Gouda, Amrit Gonugunta, Ecaterina E. Dumbrava, Timothy A. Yap, Jordi Rodon, Sarina A. Piha-Paul, Paula R. Pohlmann, Senthil Damodaran, Rashmi Murthy, Vicente Valero, Jason Mouabbi, Debu Tripathy, Aysegul A. Sahin, Hui Chen, Funda Meric-Bernstam","doi":"10.1158/1078-0432.ccr-24-3468","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-3468","url":null,"abstract":"Purpose: Trastuzumab deruxtecan (T-DXd) is currently approved for treating metastatic breast cancer (MBC) which is HER2-positive (immunohistochemistry [IHC] score of 3+ or ISH positivity) or HER2-low (IHC score of 1+ or IHC 2+/ISH negative), as well as for HER2-positive gastric cancer, HER2-mutant lung cancer, and HER2 overexpressing solid tumors. Given the increasing utilization of T-DXd, we sought to determine how HER2 receptor status might change following T-DXd therapy. Design: We retrospectively reviewed patients with MBC who received T-DXd at The University of Texas MD Anderson Cancer Center. We included patients with paired pre- and post-treatment biopsies assessed for HER2 status using IHC. Results: We included 41 patients with MBC who received treatment with T-DXd, and had paired pre- and post-treatment biopsies assessed for HER2 status using IHC. HER2 loss was observed in 11 patients (32.4% of 34 patients with pre-treatment HER2 expression (1+, 2+, or 3+)) following treatment with T-DXd. In addition to the 11 patients with HER2 loss, another 10 patients (29.4%) had a decrease in HER2 score after treatment with T-DXd. Conclusions: HER2 loss and decrease in HER2 expression are common in patients with MBC receiving treatment with T-DXd. Re-evaluation of HER2 status post-T-DXd should be considered prior to certain alternate HER2-targeted therapies which require HER2 overexpression for efficacy.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"11 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143020743","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pretargeted Trop-2 immunoPET for rapid, selective detection of pancreatic tumors","authors":"Edwin C. Pratt, Komal Mandleywala, David Bauer, Alexander Bolaender, Grace Chao, Mark A. Castanares, Emily C. Collins, Jason S. Lewis","doi":"10.1158/1078-0432.ccr-24-3098","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-3098","url":null,"abstract":"Purpose: Recent clinical advances with the approval of antibody-drug conjugates targeting Trop-2 such as sacituzumab-govitecan and datopotomab-deruxtecan have garnered tremendous interest for their therapeutic efficacy in numerous tumor types including breast and lung cancers. ImmunoPET can stratify tumor avidity, clarifying patient eligibility for ADC therapy as well as a diagnostic companion during therapy. Slow antibody circulation requires days to reach optimal imaging timepoints. To overcome this shortfall, bioorthogonal click chemistry for pretargeting can be employed, decoupling antibody circulation time and the delivery of the radionuclide. Experimental Design: Here we report the characterization of a new full-length Trop-2.2 antibody showing high affinity for Trop-2 positive cancers and leverage different site selective labeling and pretargeting radionuclide combinations to yield rapid imaging with minimal radionuclide footprint after imaging. Three pretargeting strategies for Fluorine-18, Copper-64, and Zirconium-89 were explored in addition to site specific bioconjugation. Results: We found pretargeting with [64Cu]Cu-Sar-Tz to yield the best images identifying Trop-2 positive tumors with optimal tumor-to-background ratios. Intriguingly we found the full-length antibody when directly conjugated, yielded rapid accumulation starting at 3 hours post injection and leading to over 50% injected activity per gram in the tumor before 24 hours. Conclusions: [89Zr]Zr-DFO-Trop-2 as well as pretargeting with [64Cu]Cu-Sar-Tz are viable imaging strategies to quickly identify Trop-2 positive tumors for subsequent Trop-2 therapies.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"8 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143020744","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In situ RAS:RAF binding correlates with response to KRASG12C inhibitors in KRASG12C--mutant non-small cell lung cancer.","authors":"Ryoji Kato,Hitendra S Solanki,Hilal Ozakinci,Bina Desai,Harika Gundlapalli,Yu Chi Yang,Ida Aronchik,Mallika Singh,Joseph Johnson,Andriy Marusyk,Theresa A Boyle,Eric B Haura","doi":"10.1158/1078-0432.ccr-24-3714","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-3714","url":null,"abstract":"PURPOSETherapeutic efficacy of KRASG12C(OFF) inhibitors (KRASG12Ci) in KRASG12C-mutant non-small cell lung cancer (NSCLC) varies widely. The activation status of RAS signaling in tumors with KRASG12C mutation remains unclear, as its ability to cycle between the active GTP-bound and inactive GDP-bound states may influence downstream pathway activation and therapeutic responses. We hypothesized that the interaction between RAS and its downstream effector RAF in tumors may serve as indicators of RAS activity, rendering NSCLC tumors with a high degree of RAS engagement and downstream effects more responsive to KRASG12Ci compared to tumors with lower RAS---RAF interaction.EXPERIMENTAL DESIGNWe developed a method for measuring in situ RAS binding to RAF in cancer samples using proximity ligation assays (PLAs) designed to detect panRAS-CRAF interactions.RESULTSThe panRAS-CRAF PLA signal correlated with levels of both RAS-GTP and phosphorylated ERK protein, suggesting that this assay can effectively assess active RAS signaling. We found that elevated panRAS-CRAF PLA signals were associated with increased sensitivity to KRASG12Ci in KRASG12C-mutant NSCLC cell lines, xenograft models, and patient samples. Applying a similar PLA approach to measure the interactions between EGFR and its adaptor protein GRB2 as a surrogate for EGFR activity, we found no relationship between EGFR activity and response to KRASG12Ci in the same samples.CONCLUSIONSOur study highlights the importance of evaluating in situ RAS-RAF interactions as a potential predictive biomarker for identifying NSCLC patients most likely to benefit from KRASG12Ci. The PLA developed for quantifying these interactions represents a valuable tool for guiding treatment strategies.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"9 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142991797","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MAPK pathway activating alteration and immunotherapy efficacy in squamous cell lung carcinoma: results from the randomized, prospective SQUINT trial.","authors":"Federico Cappuzzo,Biagio Ricciuti,Angelo Delmonte,Laura Bonanno,Xiaoyue Wang,Weng Kit Lye,Andreas Görtz,Kalliopi Andrikou,Alessandro Dal Maso,Gabriele Minuti,Maximilian Papi,Joao Victor Alessi,Alessandro Di Federico,Scott Rodig,Mark Magdi Awad,Giulio Metro,Ilaria Attili,Fabiana Vitiello,Sara Pilotto,Stefania Gori,Giulio Rossi,Simonetta Buglioni,Diana Giannarelli,Lorenza Landi","doi":"10.1158/1078-0432.ccr-24-2077","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-2077","url":null,"abstract":"BACKGROUNDThe role of activating alterations in the MAPK pathway in predicting immunotherapy efficacy in lung squamous cell carcinoma (LSCC) patients is largely unknown. The aims of the randomized, phase II SQUINT trial were to assess the efficacy of nivolumab plus ipilimumab (NI) versus platinum-based chemotherapy plus nivolumab (N-CT) and to identify clinically available biomarkers of response to immunotherapy in patients with advanced or metastatic LSCC.METHODSSQUINT was an open-label, randomized, parallel, non-comparative, phase II trial of NI versus N-CT in chemo-naïve, metastatic or recurrent LSCC adult patients. The study was conducted across 15 Italian centers from September 2017 to February 2022 (ClinicalTrials.gov ID: NCT03823625).RESULTS45 patients were included in the NI arm and 46 in the N-CT arm. At 12 months, the overall survival (OS) rate was 62% in the NI arm and 50% in the N-CT arm. 74 patients were included in the analyses for individual biomarkers. In patients with mutations or copy number variations of genes involved in the MAPK pathway, we observed higher response to immunotherapy (43% vs 15%), longer progression-free survival (PFS) (p=0.03) and OS (p<0.001). A higher density of CD8+PD1+ T cells (p=0.04) among MAPK-altered tumors versus wild-type, together with an increased CD8+PD1+/FOXP3 ratio (p=0.047) were observed. In the validation cohort of patients not exposed to immunotherapy, OS was similar between MAPK13 mutant and wild-type LSCC.CONCLUSIONWe showed for the first time that MAPK pathway activating alteration influences the outcome of LSCC treated with immunotherapy, highlighting the relevance of gene profiling.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"107 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142991803","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Randomized phase II study of bevacizumab with weekly anetumab ravtansine or weekly paclitaxel in platinum-resistant/refractory high grade ovarian cancer (NCI trial).","authors":"Husam A Alqaisi,David E Cohn,Jing-Yi Chern,Linda R Duska,Andrea Jewell,Bradley R Corr,Ira Seth Winer,Eugenia Girda,Marta A Crispens,Neesha C Dhani,Ainhoa Madariaga,Robert C Grant,Matthew Malaguti,Crystal Lee,Valerie Bowering,Horace Wong,Andrew Poothullil,Vanessa Speers,Lisa Wang,Philippe L Bedard,John C Brady,Andrew B Nixon,Li Chen,Claire O'Connor,William Zamboni,Tawyna McKee,Jeffrey A Moscow,Amit M Oza,Stephanie Lheureux","doi":"10.1158/1078-0432.ccr-24-3128","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-3128","url":null,"abstract":"PURPOSEMesothelin (MSLN) is highly expressed in high grade serous/ endometrioid ovarian cancers (HGOC). Anetumab ravtansine (AR) is an antibody drug conjugate directed at MSLN antigen with a tubulin polymerization inhibitor. We assessed safety, activity and pharmacokinetics of the combination AR/bevacizumab (Bev) (ARB) versus weekly paclitaxel (wP)/Bev (PB) in patients with platinum resistant/refractory HGOC (prrHGOC). Expiremental design: Following a run-in phase I study to assess ARB safety, prrHGOC patients with centrally confirmed MSLN positive expression were randomized to ARB or PB (wP 80mg/m2 with Bev 10mg/kg biweekly). Patients were stratified by platinum resistance/refractory and prior Bev. The primary endpoint was progression-free survival (PFS), secondary endpoints were overall response rate (ORR), safety, and blood-based angiome biomarker assessment. A futility analysis was planned after 35 PFS events.RESULTSThe combination of Bev (10mg/kg) biweekly with AR (2.2mg/kg) weekly was well tolerated. Regarding phase II results, mesothelin positivity was 88% and 57 pts were randomized (28 ARB, 29 PB). 42% pts received prior Bev and 23% were platinum refractory. At futility analysis, the median PFS was 5.3 and 12.7 months for ARB and PB respectively (p=0.03, HR= 2.02 [1.06-3.86]). ORR was 21% with ARB and 65% with PB. The most common treatment-related grade ≥ 3 adverse events were anemia (18%) with ARB, and neutropenia (24%) with PB. Higher baseline levels of circulating IL-6 were associated with worse PFS, and its levels decreased with PB treatment.CONCLUSIONOur study stopped at interim analysis highlighting the benefit of PB in prrHGOC as standard of care.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"205 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142991796","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CA-125 as a Biomarker in Renal Medullary Carcinoma: Integrated Molecular Profiling, Functional Characterization, and Prospective Clinical Validation.","authors":"Sandra L Grimm,Menuka Karki,Kyle A Blum,Jean-Philippe Bertocchio,Rong He,Durga N Tripathi,Niki M Zacharias,Justin M Lebenthal,Rahul A Sheth,Priya Rao,Giannicola Genovese,Zhen Lu,Robert C Bast,Davis R Ingram,Rossana Lazcano,Khalida M Wani,Wei-Lien Wang,Alexander J Lazar,Nizar M Tannir,Cheryl L Walker,Cristian Coarfa,Pavlos Msaouel","doi":"10.1158/1078-0432.ccr-24-3324","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-3324","url":null,"abstract":"PURPOSERenal medullary carcinoma (RMC) is a highly aggressive malignancy defined by the loss of the SMARCB1 tumor suppressor. It mainly affects young individuals of African descent with sickle cell trait, and it is resistant to conventional therapies used for other renal cell carcinomas. This study aimed to identify potential biomarkers for early detection and disease monitoring of RMC.EXPERIMENTAL DESIGNIntegrated profiling of primary untreated RMC tumor tissues and paired adjacent kidney controls was performed using RNA-sequencing (RNA-seq) and histone Chromatin Immunoprecipitation Sequencing (ChIP-seq). The expression of serum cancer antigen 125 (CA-125), was prospectively evaluated in 47 patients with RMC. Functional studies were conducted in RMC cell lines to assess the effects of SMARCB1 re-expression.RESULTSMUC16, encoding for CA-125, was identified as one of the top upregulated genes in RMC tissues, with concomitant enrichment of active histone marks H3K4me3 and H3K27ac at its promoter. Elevated serum CA-125 levels were found in 31 of 47 (66%) RMC patients and correlated significantly with metastatic tumor burden (p = 0.03). Functional studies in RMC cell lines demonstrated that SMARCB1 re-expression significantly reduced MUC16 expression.CONCLUSIONSThe correlation between serum CA-125 levels and metastatic burden suggests that CA-125 is a clinically relevant biomarker for RMC. These findings support further exploration of CA-125 for disease monitoring and targeted therapeutics in RMC.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"37 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142991798","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}