Journal of Clinical Oncology最新文献

{"title":"Rectal Relief: Proton Therapy's Impact on Urgency and Frequency.","authors":"Omran Saifi, Albert Attia, Bradford S Hoppe","doi":"10.1200/JCO.24.01162","DOIUrl":"10.1200/JCO.24.01162","url":null,"abstract":"","PeriodicalId":15384,"journal":{"name":"Journal of Clinical Oncology","volume":" ","pages":"3762-3763"},"PeriodicalIF":42.1,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141855582","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":"Devimistat (CPI-613) With Modified Fluorouarcil, Oxaliplatin, Irinotecan, and Leucovorin (FFX) Versus FFX for Patients With Metastatic Adenocarcinoma of the Pancreas: The Phase III AVENGER 500 Study.","authors":"Philip A Philip, Vaibhav Sahai, Nathan Bahary, Amit Mahipal, Anup Kasi, Caio Max S Rocha Lima, Angela T Alistar, Paul E Oberstein, Talia Golan, Jean-Philippe Metges, Jill Lacy, Christos Fountzilas, Charles D Lopez, Michel Ducreux, Pascal Hammel, Mohamed Salem, David Bajor, Al B Benson, Sanjeev Luther, Timothy Pardee, Eric Van Cutsem","doi":"10.1200/JCO.23.02659","DOIUrl":"10.1200/JCO.23.02659","url":null,"abstract":"<p><strong>Purpose: </strong>Metastatic pancreatic adenocarcinoma (mPC) remains a difficult-to-treat disease. Fluorouarcil, oxaliplatin, irinotecan, and leucovorin (FFX) is a standard first-line therapy for mPC for patients with a favorable performance status and good organ function. In a phase I study, devimistat (CPI-613) in combination with modified FFX (mFFX) was deemed safe and exhibited promising efficacy in mPC.</p><p><strong>Methods: </strong>The AVENGER 500 trial (ClinicalTrials.gov identifier: NCT03504423) is a global, randomized phase III trial conducted at 74 sites across six countries to investigate the efficacy and safety of devimistat in combination with mFFX (experimental arm) compared with standard-dose FFX (control arm) in treatment-naïve patients with mPC. Treatment, administered in once-every-2-weeks cycles until disease progression or intolerable toxicity, included intravenous devimistat at 500 mg/m² total per day on days 1 and 3 in the experimental arm. The primary end point of the study was overall survival (OS).</p><p><strong>Results: </strong>Five hundred and twenty-eight patients were randomly assigned (266 in the experimental arm and 262 in the control arm). The median OS was 11.10 months for devimistat plus mFFX versus 11.73 months for FFX (hazard ratio [HR], 0.95 [95% CI, 0.77 to 1.18]; <i>P</i> = .655) and median progression-free survival was 7.8 months versus 8.0 months, respectively (HR, 0.99 [95% CI, 0.76 to 1.29]; <i>P</i> = .94). Grade ≥3 treatment-emergent adverse events with >10% frequency in the devimistat plus mFFX arm versus the FFX arm were neutropenia (29.0% <i>v</i> 34.5%), diarrhea (11.2% <i>v</i> 19.6%), hypokalemia (13.1% <i>v</i> 14.9%), anemia (13.9% <i>v</i> 13.6%), thrombocytopenia (11.6% <i>v</i> 13.6%), and fatigue (10.8% <i>v</i> 11.5%), respectively.</p><p><strong>Conclusion: </strong>Devimistat in combination with mFFX did not improve long- and short-term mPC patient outcomes compared with standard FFX. There were no new toxicity signals with the addition of devimistat.</p>","PeriodicalId":15384,"journal":{"name":"Journal of Clinical Oncology","volume":" ","pages":"3692-3701"},"PeriodicalIF":42.1,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141874907","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":"Adjuvant Pertuzumab and Trastuzumab in Early Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer in the APHINITY Trial: Third Interim Overall Survival Analysis With Efficacy Update.","authors":"Sibylle Loibl, Jacek Jassem, Amir Sonnenblick, Damien Parlier, Eric Winer, Jonas Bergh, Richard D Gelber, Eleonora Restuccia, Young-Hyuck Im, Chiun-Sheng Huang, Florence Dalenc, Isabel Calvo, Marion Procter, Carmela Caballero, Emma Clark, Alice Raimbault, Robin McConnell, Estefania Monturus, Evandro de Azambuja, Henry L Gomez, Judith Bliss, Giuseppe Viale, Jose Bines, Martine Piccart","doi":"10.1200/JCO.23.02505","DOIUrl":"10.1200/JCO.23.02505","url":null,"abstract":"<p><p><i>Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in</i> JCO <i>or elsewhere, for which the primary end point has already been reported.</i>The APHINITY trial (ClinicalTrials.gov identifier: NCT01358877) previously demonstrated that pertuzumab added to adjuvant trastuzumab and chemotherapy improved invasive disease-free survival (iDFS) for patients with early human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC). Here, we report the preplanned third interim analysis of overall survival (OS) and a descriptive updated iDFS analysis with 8.4 years of median follow-up of 4,804 patients in the intent-to-treat population. The 8-year OS was 92.7% in the pertuzumab versus 92.0% in the placebo group (hazard ratio [HR], 0.83 [95% CI, 0.68 to 1.02]; <i>P</i> = .078, above the 0.006 significance threshold). The HR was 0.80 [95% CI 0.63 to 1.00] in the node-positive cohort and 0.99 [95% CI, 0.64 to 1.55] in the node-negative cohort. Updated results of 8-year iDFS in the node-positive cohort showed an absolute improvement of 4.9% favoring pertuzumab (86.1% <i>v</i> 81.2%; HR, 0.72 [95% CI, 0.60 to 0.87]). The node-negative cohort did well without adding pertuzumab (8-year iDFS and OS in the placebo group were 93.3% and 96.4%, respectively). The iDFS benefit was seen in the hormone receptor-negative (HR, 0.82 [95% CI, 0.64 to 1.06]) and HR+ cohorts (HR of 0.75 [95% CI, 0.61 to 0.92]). Despite improvement in overall iDFS, the addition of pertuzumab did not improve OS at this third interim analysis.</p>","PeriodicalId":15384,"journal":{"name":"Journal of Clinical Oncology","volume":" ","pages":"3643-3651"},"PeriodicalIF":42.1,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142288203","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":"Corticosteroids for Immune-Related Adverse Events and Checkpoint Inhibitor Efficacy: Analysis of Six Clinical Trials.","authors":"Rik J Verheijden, Jolien S de Groot, Babs O Fabriek, Miki N Hew, Anne M May, Karijn P M Suijkerbuijk","doi":"10.1200/JCO.24.00191","DOIUrl":"10.1200/JCO.24.00191","url":null,"abstract":"<p><strong>Purpose: </strong>Retrospective studies suggest that immunosuppressive treatment of immune-related adverse events (irAEs) impairs survival in patients with melanoma who received immune checkpoint inhibitors. Here, we study this association across tumor types using data from six international phase II/III registrational trials.</p><p><strong>Methods: </strong>A post hoc analysis was performed on individual patient data from the anti-programmed cell death-1 (anti-PD-1) + anti-cytotoxic T lymphocyte-associated protein-4 (anti-CTLA-4) treatment arms of six clinical trials (CheckMate-067, -142, -214, -648, -743, and -9LA). Among patients who received systemic immunosuppression for treatment-related adverse events (trAEs), associations of peak and cumulative corticosteroid dose, and use of second-line immunosuppression with overall survival (OS) and progression-free survival (PFS) were assessed using multilevel Cox regression with adjustment for age and sex.</p><p><strong>Results: </strong>Of the 1,959 patients who received anti-PD-1 + anti-CTLA-4 therapy, 834 patients who were treated with immunosuppression for trAEs were included. Eight hundred and thirty-two patients (100%) received corticosteroids and 81 patients (10%) received second-line immunosuppressants. High corticosteroid peak dose was associated with worse PFS: adjusted hazard ratio (HR_adj), 1.15 (95% CI, 1.02 to 1.29) for 1 versus 0.5 mg/kg prednisolone and HR_adj, 1.43 (95% CI, 1.05 to 1.96) for 2 versus 0.5 mg/kg. Similar effects were observed for OS: HR_adj, 1.21 (95% CI, 1.06 to 1.39) and HR_adj, 1.66 (95% CI, 1.17 to 2.37) for 1 and 2 versus 0.5 mg/kg, respectively. Cumulative corticosteroid dose was not associated with survival. HR_adj of use of second-line immunosuppression was 1.23 (95% CI, 0.90 to 1.68) for PFS and 1.25 (95% CI, 0.88 to 1.77) for OS.</p><p><strong>Conclusion: </strong>Higher corticosteroid peak dose for trAEs is associated with worse survival across tumor types, while cumulative dose is not. Too few patients received second-line immunosuppressants to confirm or reject an association with survival. These data argue for a reconsideration of irAE management approaches, starting with lower corticosteroid dose whenever feasible.</p>","PeriodicalId":15384,"journal":{"name":"Journal of Clinical Oncology","volume":" ","pages":"3713-3724"},"PeriodicalIF":42.1,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141901951","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":"Advances in Vulvar Cancer Biology and Management.","authors":"Rania Chehade, Katarzyna J Jerzak, Farideh Tavanger, Anna Plotkin, Lilian T Gien, Eric Leung, Helen Mackay","doi":"10.1200/JCO.24.01071","DOIUrl":"10.1200/JCO.24.01071","url":null,"abstract":"<p><strong>Purpose: </strong>Vulvar squamous cell carcinoma (VSCC), a rare gynecologic malignancy, has been rising in incidence. Molecular classification on the basis of human papilloma virus (HPV) and tumor protein 53 (p53) status has identified three clinically distinct subtypes, but we still treat all VSCCs the same. Here, we review molecular classification of VSCC, outline treatment landscape, and highlight potential for targeted therapies in advanced VSCC.</p><p><strong>Design: </strong>We conducted a comprehensive review of the literature on treatment of advanced VSCC with particular focus on the implications of molecular stratification on the basis of HPV and p53 status on the treatment landscape of advanced VSCC.</p><p><strong>Results: </strong>Incorporation of HPV and p53 status in locoregional treatment decision making has the potential to advise (de)escalation strategies. The role of immunotherapy, alone and in combination, requires further exploration particularly earlier in the course of the disease. In advanced stages, potential for targeted therapies in VSCCs include inhibitors of vascular endothelial growth factor, endothelial growth factor receptor, cell cycle, and DNA damage response, particularly in HPV-negative (HPV-) VSCCs. Targeting the phosphoinositide 3 kinase/mammalian target of rapamycin pathway is attractive in HPV-positive and HPV-/p53 wildtype VSCCs. Trials incorporating antibody-drug conjugates (eg, trophoblast cell-surface antigen 2, human epidermal growth factor receptor 2) should be considered, and basket trials in perineal squamous cell cancers are warranted. Preclinical models are limited and should be expanded to inform trial design.</p><p><strong>Conclusion: </strong>Like other rare cancers, vulvar cancer lags behind in the identification and optimization of precision medicine strategies. Molecular-based preclinical models and rationally designed clinical trials, incorporating high-quality translational studies, are urgently required. These trials will require international collaboration to ensure feasibility and improvement of outcomes for women diagnosed with this disease.</p>","PeriodicalId":15384,"journal":{"name":"Journal of Clinical Oncology","volume":" ","pages":"JCO2401071"},"PeriodicalIF":42.1,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142557958","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":"Large-Scale Pharmacogenomics Analysis of Patients With Cancer Within the 100,000 Genomes Project Combining Whole-Genome Sequencing and Medical Records to Inform Clinical Practice.","authors":"Ivone U S Leong, Claudia P Cabrera, Valentina Cipriani, Paul J Ross, Richard M Turner, Alex Stuckey, Sonali Sanghvi, Dorota Pasko, Loukas Moutsianas, Christopher A Odhams, Greg S Elgar, Georgia Chan, Adam Giess, Susan Walker, Rebecca E Foulger, Eleanor M Williams, Louise C Daugherty, Antonio Rueda-Martin, Daniel J Rhodes, Olivia Niblock, Alexandra Pickard, Lauren Marks, Sarah E A Leigh, Matthew J Welland, Marta Bleda, Catherine Snow, Zandra Deans, Nirupa Murugaesu, Richard H Scott, Michael R Barnes, Matthew A Brown, Augusto Rendon, Sue Hill, Alona Sosinsky, Mark J Caulfield, Ellen M McDonagh","doi":"10.1200/JCO.23.02761","DOIUrl":"10.1200/JCO.23.02761","url":null,"abstract":"<p><strong>Purpose: </strong>As part of the 100,000 Genomes Project, we set out to assess the potential viability and clinical impact of reporting genetic variants associated with drug-induced toxicity for patients with cancer recruited for whole-genome sequencing (WGS) as part of a genomic medicine service.</p><p><strong>Methods: </strong>Germline WGS from 76,805 participants was analyzed for pharmacogenetic (PGx) variants in four genes (<i>DPYD</i>, <i>NUDT15</i>, <i>TPMT</i>, <i>UGT1A1</i>) associated with toxicity induced by five drugs used in cancer treatment (capecitabine, fluorouracil, mercaptopurine, thioguanine, irinotecan). Linking genomic data with prescribing and hospital incidence records, a phenome-wide association study (PheWAS) was performed to identify whether phenotypes indicative of adverse drug reactions (ADRs) were enriched in drug-exposed individuals with the relevant PGx variants. In a subset of 7,081 patients with cancer, <i>DPYD</i> variants were reported back to clinicians and outcomes were collected.</p><p><strong>Results: </strong>We identified clinically relevant PGx variants across the four genes in 62.7% of participants in our cohort. Extending this to annual prescription numbers in England for the drugs affected by these PGx variants, approximately 14,540 patients per year could potentially benefit from a reduced dose or alternative drug to reduce the risk of ADRs. Validating PGx associations in a real-world data set, we found a significant association between PGx variants in <i>DPYD</i> and toxicity-related phenotypes in patients treated with capecitabine or fluorouracil. Reported <i>DPYD</i> variants were deemed informative for clinical decision making in a majority of cases.</p><p><strong>Conclusion: </strong>Reporting PGx variants from germline WGS relevant to patients with cancer alongside primary findings related to their cancer can be clinically informative, informing prescribing to reduce the risk of ADRs. Extending the range of actionable variants to those found in patients of non-European ancestry is important and will extend the potential clinical impact.</p>","PeriodicalId":15384,"journal":{"name":"Journal of Clinical Oncology","volume":" ","pages":"JCO2302761"},"PeriodicalIF":42.1,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142557960","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":"Cost-Effectiveness of Total Neoadjuvant Therapy With Selective Nonoperative Management for Locally Advanced Rectal Cancer: Analysis of Data From the Organ Preservation for Rectal Adenocarcinoma Trial.","authors":"Maria Widmar, Mason McCain, Akriti Mishra Meza, Charles Ternent, Andrew Briggs, Julio Garcia-Aguilar","doi":"10.1200/JCO.24.00681","DOIUrl":"10.1200/JCO.24.00681","url":null,"abstract":"<p><strong>Purpose: </strong>The clinical efficacy of total neoadjuvant therapy (TNT) followed by selective nonoperative management (NOM) for locally advanced rectal cancer (LARC) was examined in the Organ Preservation for Rectal Adenocarcinoma (OPRA) trial. We investigated the cost and quality-of-life implications of adopting this treatment approach.</p><p><strong>Methods: </strong>We analyzed clinical, cost, and quality-of-life outcomes for TNT with selective NOM in comparison with chemoradiotherapy (CRT)-surgery-adjuvant chemotherapy (standard of care [SOC]) using data from OPRA, prospective cohorts, and published studies. Cost-effectiveness was evaluated over varying willingness-to-pay thresholds, and sensitivity analyses evaluated cost-effectiveness for different surgical contexts and SOC variants as well as a 10-year time horizon.</p><p><strong>Results: </strong>SOC was dominated by TNT with selective NOM in the base case analysis. TNT in which CRT was followed by consolidation chemotherapy (CNCT) was the least costly at $89,712 in Medicare proportionate US dollars (MP$), followed by TNT in which induction chemotherapy was followed by CRT (INCT) at MP$90,259 and SOC at MP$98,755. INCT was the preferred strategy, with 4.56 quality-adjusted life years, followed by CNCT at 4.42 and SOC at 4.29. TNT with selective NOM dominated SOC in all sensitivity analyses except when SOC omitted adjuvant chemotherapy without an impact on disease-free survival. CNCT was more cost effective than SOC when the proportion of patients entering NOM after TNT was ≥22% or ≥43%, for SOC with and without adjuvant therapy, both well below the rates seen in OPRA.</p><p><strong>Conclusion: </strong>TNT with selective NOM is cost effective. The cost-effectiveness of CNCT with NOM relative to SOC is dependent on CNCT being made available to a sufficiently large proportion of patients with LARC. Additional analyses are needed to validate these findings from a societal perspective and in the context of other emerging treatment paradigms for LARC.</p>","PeriodicalId":15384,"journal":{"name":"Journal of Clinical Oncology","volume":" ","pages":"JCO2400681"},"PeriodicalIF":42.1,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142557959","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":"Phase II Trial of Enfortumab Vedotin in Patients With Previously Treated Advanced Head and Neck Cancer.","authors":"Paul L Swiecicki, Emrullah Yilmaz, Ari Joseph Rosenberg, Takao Fujisawa, Justine Yang Bruce, Changting Meng, Michele Wozniak, Yongyun Zhao, Michael Mihm, Jason Kaplan, Seema Gorla, Jessica L Geiger","doi":"10.1200/JCO.24.00646","DOIUrl":"10.1200/JCO.24.00646","url":null,"abstract":"<p><strong>Purpose: </strong>Despite advances in immunotherapy, unresectable recurrent/metastatic head and neck cancer (HNC) carries a poor prognosis, and effective treatments are needed. As nectin-4 is widely expressed in HNC, enfortumab vedotin (EV), a nectin-4-directed antibody-drug conjugate, was explored in HNC in EV-202 (ClinicalTrials.gov identifier: NCT04225117).</p><p><strong>Methods: </strong>This open-label, multicohort, phase II study evaluated intravenous EV 1.25 mg/kg on days 1, 8, and 15 of each 28-day cycle. In the HNC cohort, eligible patients had recurrent/metastatic HNC and had received platinum-based therapy for locally advanced/metastatic disease and a PD-1/PD-L1 inhibitor. The primary end point was investigator-assessed confirmed objective response rate (ORR) per RECIST version 1.1. Secondary end points were investigator-assessed duration of response (DOR), disease control rate (DCR), and progression-free survival (PFS); overall survival (OS); and safety.</p><p><strong>Results: </strong>The primary analysis included 46 patients; all received EV (median follow-up, 9.3 months). Most patients (52.2%) had ≥3 previous lines of systemic therapy in the metastatic setting. Confirmed ORR was 23.9%, DCR was 56.5%, and median DOR was not reached (median DOR was 9.4 months at a later data cutoff [median follow-up, 11.3 months]). Median PFS and OS were 3.9 and 6.0 months, respectively. Treatment-related adverse events (TRAEs) occurring in >20% of patients were alopecia (28.3%), fatigue (26.1%), and peripheral sensory neuropathy (23.9%). Sixteen patients (34.8%) experienced grade ≥3 TRAEs; anemia and decreased neutrophil count occurred in ≥1 patient (both n = 2; 4.3%).</p><p><strong>Conclusion: </strong>EV demonstrated antitumor activity in heavily pretreated HNC. Safety was consistent with the known safety profile of EV; no new safety signals were identified. These data support further evaluation of EV for advanced HNC not amenable to definitive local therapy.</p>","PeriodicalId":15384,"journal":{"name":"Journal of Clinical Oncology","volume":" ","pages":"JCO2400646"},"PeriodicalIF":42.1,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142557961","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":"Onvansertib in Combination With Chemotherapy and Bevacizumab in Second-Line Treatment of <i>KRAS</i>-Mutant Metastatic Colorectal Cancer: A Single-Arm, Phase II Trial.","authors":"Daniel H Ahn, Maya Ridinger, Timothy L Cannon, Lawrence Mendelsohn, Jason S Starr, Joleen M Hubbard, Anup Kasi, Afsaneh Barzi, Errin Samuëlsz, Anju Karki, Ramanand A Subramanian, Divora Yemane, Roy Kim, Chu-Chiao Wu, Peter J P Croucher, Tod Smeal, Fairooz F Kabbinavar, Heinz-Josef Lenz","doi":"10.1200/JCO-24-01266","DOIUrl":"10.1200/JCO-24-01266","url":null,"abstract":"<p><strong>Purpose: </strong>This phase II study evaluated the efficacy and tolerability of onvansertib, a polo-like kinase 1 (PLK1) inhibitor, in combination with fluorouracil, leucovorin, and irinotecan (FOLFIRI) + bevacizumab for the second-line treatment of <i>KRAS</i>-mutant metastatic colorectal cancer (mCRC).</p><p><strong>Patients and methods: </strong>This multicenter, open-label, single-arm study enrolled patients with <i>KRAS</i>-mutated mCRC previously treated with oxaliplatin and fluorouracil with or without bevacizumab. Patients received onvansertib (15 mg/m² once daily on days 1-5 and 15-19 of a 28-day cycle) and FOLFIRI + bevacizumab (days 1 and 15). The primary end point was the objective response rate (ORR), and secondary endpoints included progression-free survival (PFS), duration of response (DOR), and tolerability. Translational and preclinical studies were conducted in <i>KRAS</i>-mutant CRC.</p><p><strong>Results: </strong>Among the 53 patients treated, the confirmed ORR was 26.4% (95% CI, 15.3 to 40.3). The median DOR was 11.7 months (95% CI, 9.4 to not reached). Grade 3/4 adverse events were reported in 62% of patients. A post hoc analysis revealed that patients with no prior bevacizumab treatment had a significantly higher ORR and longer PFS compared with patients with prior bevacizumab treatment: ORR of 76.9% versus 10.0% (odds ratio of 30.0, <i>P</i> < .001) and median PFS of 14.9 months versus 6.6 months (hazard ratio of 0.16, <i>P</i> < .001). Our translational findings support that prior bevacizumab exposure contributes to onvansertib resistance. Preclinically, we showed that onvansertib inhibited the hypoxia pathway and exhibited robust antitumor activity in combination with bevacizumab through the inhibition of angiogenesis.</p><p><strong>Conclusion: </strong>Onvansertib in combination with FOLFIRI + bevacizumab showed significant activity in the second-line treatment of patients with <i>KRAS</i>-mutant mCRC, particularly in patients with no prior bevacizumab treatment. These findings led to the evaluation of the combination in the first-line setting (ClinicalTrails.gov identifier: NCT06106308).</p>","PeriodicalId":15384,"journal":{"name":"Journal of Clinical Oncology","volume":" ","pages":"JCO2401266"},"PeriodicalIF":42.1,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142545725","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":"Second Primary Cancer Risks After Breast Cancer in <i>BRCA1</i> and <i>BRCA2</i> Pathogenic Variant Carriers.","authors":"Isaac Allen, Hend Hassan, Yvonne Walburga, Catherine Huntley, Lucy Loong, Tameera Rahman, Sophie Allen, Alice Garrett, Bethany Torr, Andrew Bacon, Craig Knott, Sophie Jose, Sally Vernon, Margreet Lüchtenborg, Joanna Pethick, Francesco Santaniello, Shilpi Goel, Ying-Wen Wang, Katrina Lavelle, Fiona McRonald, Diana Eccles, Eva Morris, Steven Hardy, Clare Turnbull, Marc Tischkowitz, Paul Pharoah, Antonis C Antoniou","doi":"10.1200/JCO.24.01146","DOIUrl":"10.1200/JCO.24.01146","url":null,"abstract":"<p><strong>Purpose: </strong>Second primary cancer (SPC) risks after breast cancer (BC) in <i>BRCA1/BRCA2</i> pathogenic variant (PV) carriers are uncertain. We estimated relative and absolute risks using a novel linkage of genetic testing data to population-scale National Disease Registration Service and Hospital Episode Statistics electronic health records.</p><p><strong>Methods: </strong>We followed 25,811 females and 480 males diagnosed with BC and tested for germline <i>BRCA1/BRCA2</i> PVs in NHS Clinical Genetics centers in England between 1995 and 2019 until SPC diagnosis, death, migration, contralateral breast/ovarian surgery plus 1 year, or the 31st of December 2020. We estimated standardized incidence ratios (SIRs) using English population incidences, hazard ratios (HRs) comparing carriers to noncarriers using Cox regression, and Kaplan-Meier 10-year cumulative risks.</p><p><strong>Results: </strong>There were 1,840 <i>BRCA1</i> and 1,750 <i>BRCA2</i> female PV carriers. Compared with population incidences, <i>BRCA1</i> carriers had elevated contralateral BC (CBC; SIR, 15.6 [95% CI, 11.8 to 20.2]), ovarian (SIR, 44.0 [95% CI, 31.4 to 59.9]), combined nonbreast/ovarian (SIR, 2.18 [95% CI, 1.59 to 2.92]), colorectal (SIR, 4.80 [95% CI, 2.62 to 8.05]), and endometrial (SIR, 2.92 [95% CI, 1.07 to 6.35]) SPC risks. <i>BRCA2</i> carriers had elevated CBC (SIR, 7.70 [95% CI, 5.45 to 10.6]), ovarian (SIR, 16.8 [95% CI, 10.3 to 26.0]), pancreatic (SIR, 5.42 [95% CI, 2.09 to 12.5]), and combined nonbreast/ovarian (SIR, 1.68 [95% CI, 1.24 to 2.23]) SPC risks. Compared with females without <i>BRCA1/BRCA2</i> PVs on testing, <i>BRCA1</i> carriers had elevated CBC (HR, 3.60 [95% CI, 2.65 to 4.90]), ovarian (HR, 33.0 [95% CI, 19.1 to 57.1]), combined nonbreast/ovarian (HR, 1.45 [95% CI, 1.05 to 2.01]), and colorectal (HR, 2.93 [95% CI, 1.53 to 5.62]) SPC risks. <i>BRCA2</i> carriers had elevated CBC (HR, 2.40 [95% CI, 1.70 to 3.40]), ovarian (HR, 12.0 [95% CI, 6.70 to 21.5]), and pancreatic (HR, 3.56 [95% CI, 1.34 to 9.48]) SPC risks. Ten-year cumulative CBC, ovarian, and combined nonbreast/ovarian cancer risks were 16%/6.3%/7.8% (<i>BRCA1</i> carriers), 12%/3.0%/6.2% (<i>BRCA2</i> carriers), and 3.6%/0.4%/4.9% (noncarriers). Male <i>BRCA2</i> carriers had higher CBC (HR, 13.1 [95% CI, 1.19 to 146]) and prostate (HR, 5.61 [95% CI, 1.96 to 16.0]) SPC risks than noncarriers.</p><p><strong>Conclusion: </strong>Survivors of BC carrying <i>BRCA1</i> and <i>BRCA2</i> PVs are at high SPC risk. They may benefit from enhanced surveillance and risk-reduction measures.</p>","PeriodicalId":15384,"journal":{"name":"Journal of Clinical Oncology","volume":" ","pages":"JCO2401146"},"PeriodicalIF":42.1,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7616773/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142545726","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}