JCO oncology advances最新文献

{"title":"Increasing Cervical Cancer Rates Among Women Age 35-54 Years in Canada: Age-Specific Cervical Cancer Incidence Trends in Canada, 1992-2022.","authors":"Ioana A Nicolau, Matthew T Warkentin, Kirk Graff, Corinne Doll, Heather Bryant, Darren R Brenner","doi":"10.1200/OA-24-00101","DOIUrl":"10.1200/OA-24-00101","url":null,"abstract":"<p><strong>Purpose: </strong>The vast majority of cervical cancer is preventable through human papillomavirus vaccination and screening with cytology or DNA testing. After decades of progress, recent cervical cancer trends in Western populations show a plateau or modest increase in incidence rates. Further investigation is required to understand the drivers of these emerging trends. In this study, we examined age-specific cervical cancer incidence rates in Canada from 1992 to 2022.</p><p><strong>Methods: </strong>Data were obtained from the Canadian Cancer Registry maintained by Statistics Canada, which included cancer cases, population counts, and incidence rates of cervical cancer by age and province for the period 1992 to 2022. Joinpoint regression analysis was used to estimate temporal incidence trends across age groups.</p><p><strong>Results: </strong>Cervical cancer incidence rates in Canada decreased among women age 25-34 years and those 65 years and older since 1992. Incidence rates among women age 35-44 years and 45-54 years have increased by 1.1% (95% CI, 0.5 to 2.5) and 1.6% (95% CI, -0.1 to 8.6) per year since 2001 and 2012, respectively. In 2022, the highest incidence rate of cervical cancer was among women age 35-44 years (18.1 per 100,000 women), which is comparable with rates in 1992.</p><p><strong>Conclusion: </strong>Cervical cancer incidence rates have been increasing in recent years among women age 35-54 years. This cohort may be falling into a cancer prevention gap. Targeted public health interventions are warranted to address the rising incidence of cervical cancer among this cohort of Canadian women.</p>","PeriodicalId":520350,"journal":{"name":"JCO oncology advances","volume":"2 1","pages":"e2400101"},"PeriodicalIF":0.0,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12258797/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144645144","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phase I Trial to Evaluate the Safety of Intralesional Nivolumab Therapy for Limited Cutaneous Kaposi Sarcoma.","authors":"Chia-Ching J Wang, Alexander Bang, Sona Chowdhury, Kieron S Leslie, Ursula E Lang, Michiko Shimoda, Timothy J Henrich, Rebecca Hoh, Steve G Deeks, Chao Wang, Amelia N Deitchman, Paul Couey, Toby Maurer","doi":"10.1200/OA-24-00098","DOIUrl":"10.1200/OA-24-00098","url":null,"abstract":"<p><strong>Purpose: </strong>Intralesional vinblastine can induce regression of Kaposi sarcoma (KS), but it is often painful. We conducted a phase I trial to evaluate the safety and tolerability of intralesional injections of nivolumab to treat cutaneous KS.</p><p><strong>Patients and methods: </strong>We enrolled participants with limited cutaneous KS and injected 1 mL (10 mg) of nivolumab into target KS lesions once every 2 weeks for four doses, with optional extension to total of eight doses. Skin biopsy of a target KS lesion was performed at screening and at week 26. The primary end point was safety; the secondary end point was KS response by AIDS Clinical Trials Group criteria.</p><p><strong>Results: </strong>Between May 2018 and December 2020, 12 cis-gender men (six living with HIV and six without HIV) were enrolled. Baseline median CD4⁺ T-cell count was 550 and 706 cells/uL for those with and without HIV, respectively. No grade 3 or higher treatment-related adverse events (including autoimmune events) were reported. Three participants without HIV had complete resolution of the injected lesion(s). All participants had a reduction of HHV-8-positive cells in their skin biopsies at week 26. Four participants had a relative increase in the infiltrating CD8⁺ T cells in skin biopsies after treatment. PD-1 and PD-L1 by immunohistochemistry did not change between the pre- and post-treatment skin biopsies. The percentage of circulating CD4⁺ and CD8⁺ T cells expressing PD-1 decreased from 23.8% to 19.2% before treatment to 10.9% and 9.4% before the third intralesional nivolumab injection, respectively. The frequency of PD-1 expressing lymphocytes returned to baseline level at 26 weeks after the last injection.</p><p><strong>Conclusion: </strong>Intralesional nivolumab was safe and well-tolerated in this population of men with limited cutaneous KS.</p>","PeriodicalId":520350,"journal":{"name":"JCO oncology advances","volume":"2 1","pages":"e2400098"},"PeriodicalIF":0.0,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12244976/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144629207","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of the COVID-19 Pandemic Mitigation Strategies on Cancer Treatment Trials: A Meta-Analysis of Industry and National Cancer Institute Studies.","authors":"Joseph M Unger, Hillary S Andrews, Laura A Levit, Brittany A McKelvey, Mark Stewart, Beverly Canin, Keith Flaherty, Denise Kimball, Therica Miller, Adedayo Onitilo, Suanna Bruinooge, Elizabeth Garrett-Mayer, Caroline Schenkel","doi":"10.1200/OA-25-00021","DOIUrl":"10.1200/OA-25-00021","url":null,"abstract":"<p><strong>Purpose: </strong>The onset of the COVID-19 pandemic in early 2020 disrupted the conduct of cancer clinical trials. In response, federal agencies allowed more flexibility for trial recruitment and patient follow-up. A key question is whether the benefits of adopting these strategies outweigh the potential detriments to quality metrics.</p><p><strong>Methods: </strong>A joint ASCO and Friends of Cancer Research task force invited industry and National Cancer Institute trial sponsors to contribute deidentified trial-level aggregate data on enrollment, major protocol deviations, dropouts, and severe adverse events (Common Terminology Criteria for Adverse Events grade 3-5). These quality metrics were examined as proportions of participants at risk during the pre-COVID-19 (January 2017-February, 2020), initial wave (March-April, 2020), initial recovery (May-December, 2020), and secondary recovery (January 2021-December 2022) periods. Multilevel beta-regression was used, adjusting for phase; study and sponsor were treated as random effects. Indicator variables were used with pre-COVID-19 as the reference.</p><p><strong>Results: </strong>Ten sponsors contributed 67 analyzable trials with N = 12,000 US-based participants. Enrollment odds decreased 49% in the initial wave (odds ratio [OR], 0.51 [95% CI, 0.30 to 0.86], <i>P</i> = .01) but recovered to pre-COVID-19 levels by 2021-2022 (OR, 1.01 [95% CI, 0.56 to 1.81], <i>P</i> = .97). Major protocol deviations, dropouts, and severe toxicity all had a lower incidence in the initial wave compared with pre-COVID-19; these outcomes were also less frequent (<i>P</i> < .05) in the initial recovery period but returned to pre-COVID-19 levels by 2021-2022.</p><p><strong>Conclusion: </strong>In this multicollaborator evaluation, large declines in enrollment, major protocol deviations, dropouts, and severe toxicity during the acute phase of the pandemic all returned to pre-COVID-19 levels by 2021-2022. These findings highlight the impact of the temporary disruption to trial conduct during the pandemic's peak, but suggest that pandemic-related procedural flexibility did not result in long-term reduced data quality. Sponsors and regulators should consider broader adaptation of trial flexibilities moving forward.</p>","PeriodicalId":520350,"journal":{"name":"JCO oncology advances","volume":"2 1","pages":"e2500021"},"PeriodicalIF":0.0,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12178165/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144478499","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"More Frequent than Annual Administration of COVID-19 Vaccination May Be Appropriate for Patients With Cancer.","authors":"Mini Kamboj, M Kelsey Kirkwood, Kari Bohlke, Julie R Gralow, Elizabeth Garrett-Mayer, Charu Aggarwal","doi":"10.1200/OA-24-00107","DOIUrl":"10.1200/OA-24-00107","url":null,"abstract":"","PeriodicalId":520350,"journal":{"name":"JCO oncology advances","volume":"2 1","pages":"e2400107"},"PeriodicalIF":0.0,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12144529/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144251851","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Patient-Reported Outcomes During Pelvic Radiation Therapy: A Secondary Analysis on Sexual Function From NRG-RTOG 1203.","authors":"Kelsey L Corrigan, Rebecca Paulus, Ann H Klopp, Lari B Wenzel, Anamaria R Yeung, J Spencer Thompson, Desiree E Doncals, Vijayananda Kundapur, Nancy H Wiggers, Dasarahally S Mohan, Sharad A Ghamande, Shannon N Westin, Kara L Schnarr, Michael L Haas, David K Gaffney, Steven E Waggoner, Pamela J Vanderwall, Noha T Jastaniyah, Stephanie L Pugh, Lisa A Kachnic","doi":"10.1200/OA-24-00088","DOIUrl":"https://doi.org/10.1200/OA-24-00088","url":null,"abstract":"<p><strong>Purpose: </strong>NRG-RTOG 1203 reported that intensity-modulated radiation therapy (IMRT) reduced patient-reported GI toxicities in patients with cervical/endometrial cancer receiving postoperative RT, compared with 3-dimensional conformal radiation therapy (3DRT). We conducted a secondary analysis of patient-reported sexual function (PR-SF) among treatment groups to identify factors associated with sexual dysfunction.</p><p><strong>Methods and materials: </strong>Patients on NRG-RTOG 1203 were randomly assigned to 3DRT versus IMRT and completed Patient-Reported Outcomes (PRO)-Common Terminology Criteria for Adverse Events (CTCAE) and FACT-Cx surveys at baseline, week 5 of RT, and at 4-6 weeks, 1 year, and 3 years after RT. Patient responses to FACT-Cx sexual function questions were analyzed. The between-arm frequency and severity of responses and their comparison with PRO-CTCAE GI toxicity were tested using chi-square tests. A repeated-measures logistic regression model was used to determine the impact of clinical and treatment factors on PR-SF.</p><p><strong>Results: </strong>Two hundred thirty-six patients completed PR-SF questions; 125 (53%) received 3DRT and 111 (47%) IMRT. There were no significant differences in PR-SF between groups (<i>P</i> > .05). After RT, responses to \"I am afraid to have sex\" and \"I am interested in sex\" significantly improved over time (<i>P</i> = .007 and <i>P</i> = .03, respectively). At 1 year after RT, women with interference from abdominal pain were more bothered by odor from the vagina versus women with no interference of abdominal pain (5% <i>v</i> 0%, <i>P</i> = .006). Additionally, at 1 year after RT, women with no severity of abdominal pain or no interference from abdominal pain liked their body appearance more versus women with at least some abdominal pain or some interference from abdominal pain (34% <i>v</i> 13%, <i>P</i> = .003 and 32% <i>v</i> 6%, <i>P</i> = .001, respectively).</p><p><strong>Conclusion: </strong>PR-SF was similar between treatment groups. After RT, fear of sex declined and interest in sex improved over time. Women with GI toxicity after RT completion are at risk for worse sexual function.</p>","PeriodicalId":520350,"journal":{"name":"JCO oncology advances","volume":"2 1","pages":"e2400088"},"PeriodicalIF":0.0,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12071503/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144083141","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Underinvested, Under-Referred, and Underserved: Applying a Gender Equity Continuum Framework in Cancer Control Continuum Programs and Policies to Expand to Transgender and Nonbinary Populations.","authors":"Arjee Javellana Restar, Ruby Lucas, Scout Nfn, Ash B Alpert, Amanda Phipps, Grace Wang, Don Operario, Asa Radix, Leigh Ann van der Merwe, Sara Lindström, Avery Everhart, Kristi E Gamarel, Carl G Streed","doi":"10.1200/OA.24.00023","DOIUrl":"10.1200/OA.24.00023","url":null,"abstract":"<p><p>Gender-inclusive and gender-specific approaches are critically needed in cancer control continuum services to recognize and meet the needs of transgender and nonbinary (trans) populations. Current research, programs, and policies largely cater to cisgender populations and subscribe to a binary, gendered cisnormative ideology, both within health care systems and insurance policies, leaving trans people's cancer prevention and treatment needs neglected. Such disparities can be attributed to the significant gap in funding and research to address trans cancer prevention and treatment. We discuss the research, program, and policy implications of cisnormative practices and provide recommendations for promoting gender-inclusive and specific services across the cancer control continuum with the goal of eliminating cancer disparities and improving cancer outcomes for people of all gender groups, including trans populations.</p>","PeriodicalId":520350,"journal":{"name":"JCO oncology advances","volume":"2 1","pages":"e2400023"},"PeriodicalIF":0.0,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12068552/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144035159","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular Characterization and Clinical Outcomes of Pancreatic Neuroendocrine Neoplasms Harboring PAK4-NAMPT Alterations.","authors":"Ibrahim Azar, Husain Yar Khan, Sahar F Bannoura, Nishant Gandhi, Md Hafiz Uddin, Misako Nagasaka, Jun Gong, Bassel Nazha, Khalil Choucair, Nikhil Vojjala, Moh'd M Khushman, Heloisa P Soares, Wafik S El-Deiry, Philip Agop Philip, Bassel El-Rayes, Herbert Chen, Emil Lou, Irfana Muqbil, Alex Patrick Farrell, Jeffrey Swensen, Matthew James Oberley, Chadi Nabhan, Sanjay Goel, Anthony F Shields, Ramzi M Mohammad, Boris C Pasche, Asfar S Azmi","doi":"10.1200/OA-24-00032","DOIUrl":"https://doi.org/10.1200/OA-24-00032","url":null,"abstract":"<p><strong>Purpose: </strong>The mammalian target of rapamycin (mTOR) inhibitor everolimus is US Food and Drug Administration-approved for advanced pancreatic neuroendocrine neoplasms (pNENs), yet resistance is common, necessitating the identification of resistance mechanisms for effective treatment strategies. Previous studies suggest that targeting the aberrant expression of mTOR regulators p21-activated kinase 4 (PAK4) and nicotinamide phosphoribosyl transferase (NAMPT) sensitizes pNENs to everolimus. In this study, we queried a large real-world data set of pNENs, characterizing the molecular and immune landscapes, as well as the clinical outcomes associated with aberrant PAK4 and NAMPT expression.</p><p><strong>Methods: </strong>Two-hundred and ninety-four pNEN cases were analyzed using next-generation sequencing and whole-exome/whole-transcriptome sequencing. We stratified patients into clusters on the basis of median cutoff.</p><p><strong>Results: </strong>High expression of genes activated in response to mTOR activation was found in NAMPT-high and PAK4-high groups. Enrichment of PI3K/AKT/mTOR and glycolysis pathways was observed in these tumors. Higher mutation rates in multiple endocrine neoplasia type 1, alpha thalassemia/mental retardation syndrome X-linked, TSC2, SETD2, and CCNE1 were observed in high NAMPT and PAK4 clusters. Immune analysis revealed enrichment in inflammatory response pathways, IL2/STAT5 signaling, and immune checkpoint genes. Increased neutrophils, natural killer cells, and macrophages were found in PAK4-high/NAMPT-high tumors. Analysis of real-world patient data revealed that high PAK4 (<i>P</i> = .0428) or NAMPT (<i>P</i> = .0002) expression individually correlated with lower overall survival in all neuroendocrine neoplasms (NEN) cohorts, while the combined high expression of both was associated with the worst outcomes (<i>P</i> = .0002). Similar trends were observed in pancreatic NEN cohorts.</p><p><strong>Conclusion: </strong>Our study demonstrates that PAK4-high/NAMPT-high pNENs are associated with distinct molecular and immune profiles. Further investigation is warranted to determine if dual PAK4 and NAMPT blockade enhances the efficacy of immunotherapeutics.</p>","PeriodicalId":520350,"journal":{"name":"JCO oncology advances","volume":"2 1","pages":"e2400032"},"PeriodicalIF":0.0,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12052073/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144050737","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multiomic Characterization of <i>RCC1</i> and <i>RCC2</i> Expression and Their Association With Molecular Alterations, Immune Phenotypes, and Cancer Outcomes.","authors":"Misako Nagasaka, Brian Warnecke, Sai-Hong Ignatius Ou, Sahar F Bannoura, Chul Kim, Andrew Elliott, Balazs Halmos, Dave Hoon, Sourat Darabi, Ammar Sukari, Milan Radovich, Emil Lou, George Sledge, Wafik El-Deiry, Mohammed Najeeb Al-Hallak, Boris C Pasche, Asfar S Azmi","doi":"10.1200/OA-24-00033","DOIUrl":"https://doi.org/10.1200/OA-24-00033","url":null,"abstract":"<p><strong>Purpose: </strong>Regulator of chromosome condensation 1 (<i>RCC1</i>) and <i>RCC2</i> have been shown to play important roles in the regulation of cell cycle, DNA damage response, and nucleocytoplasmic transport.</p><p><strong>Materials and methods: </strong>DNA (592-gene or whole exome) and RNA (whole transcriptome) sequencing was performed at Caris Life Sciences (Phoenix, AZ). Samples were stratified by <i>RCC1</i> expression quartile thresholds (Q1: low, Q4: high) for small cell lung cancer (SCLC; n = 876), non-small cell lung cancer (NSCLC; n = 21,603), gastric cancer (GC; n = 1,908), pancreatic cancer (PC; n = 5,071), and colorectal cancer (CRC; n = 14,892). Statistical significance was determined using chi-square and Wilcoxon rank-sum tests and adjusted for multiple comparisons (*<i>P</i> < .05). Corresponding analyses were run for <i>RCC2</i>.</p><p><strong>Results: </strong>Median <i>RCC1</i> mRNA expression was highest in SCLC (14.3 transcript per million [TPM]), followed by GC (9.9), NSCLC (9.9), CRC (9.8), and PC (6.9). Similar to <i>RCC1</i>, the median <i>RCC2</i> expressions were highest in SCLC (36.2 TPM). Tumor mutational burden-high rates were positively associated with increasing <i>RCC1</i> expression quartiles (Q1-4) in NSCLC (31%-41%), GC (7%-22%), and CRC (5%-17%) and with increasing <i>RCC2</i> expression in NSCLC and CRC only. Higher expression with <i>RCC1</i> and <i>RCC2</i> was associated with worse overall survival in NSCLC (hazard ratio [HR] for <i>RCC1</i> and <i>RCC2</i> were 1.3 and 1.3, respectively), PC (HR for <i>RCC1</i> and <i>RCC2</i> were 1.5 and 1.12, respectively), and CRC (HR for <i>RCC1</i> and <i>RCC2</i> were 1.3 and 1.03, respectively).</p><p><strong>Conclusion: </strong><i>RCC1</i> and <i>RCC2</i> expression is a negative prognostic marker in NSCLC, PC, and CRC. Further studies to investigate <i>RCC1</i> and <i>RCC2</i> function at the molecular level may provide opportunities for novel targeted drug development.</p>","PeriodicalId":520350,"journal":{"name":"JCO oncology advances","volume":"2 1","pages":"00022"},"PeriodicalIF":0.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12052079/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144002152","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ACR-368, a CHK1/2 Kinase Inhibitor, in Patients With Relapsed or Refractory Desmoplastic Small Round Cell Tumor: Phase I/II Trial Results.","authors":"Emily K Slotkin, Audrey Mauguen, Filemon S Dela Cruz, Michael V Ortiz, Viswatej Avutu, Paul A Meyers, Leonard H Wexler, Tara J O'Donohue, Michael D Kinnaman, Ciara M Kelly, Sandra P D'Angelo, Mary Lou Keohan, Mrinal M Gounder, Katherine Thornton, Benjamin A Nacev, Ping Chi, Evan Rosenbaum, Mark Dickson, Sagarika Pachhal, Romel Somwar, Marc Ladanyi, Caroline Robb, Neeta Pandit-Taskar, Sinchun Hwang, Anita Price, Gerald Behr, Damon R Reed, Alex Kentsis, Andrew L Kung, Julia Glade Bender, William D Tap","doi":"10.1200/OA-24-00095","DOIUrl":"https://doi.org/10.1200/OA-24-00095","url":null,"abstract":"<p><strong>Purpose: </strong>We hypothesized that ACR-368 (prexasertib) would be active in desmoplastic small round cell tumor (DSRCT) because of favorable responses in preclinical models.</p><p><strong>Methods: </strong>Preclinical work identified ACR-368 activity in DSRCT, and a phase I/II trial of ACR-368 and irinotecan in patients 12 months and older with relapsed/refractory DSRCT was conducted. The primary objectives were determination of recommended phase II dose (RP2D) and best overall response rate (ORR) at the RP2D in DSRCT, with ≥3 of 16 responses considered promising.</p><p><strong>Results: </strong>Preclinical data confirmed ACR-368 as potentially therapeutic in DSRCT, and 19 patients were enrolled in a subsequent clinical trial. Treatment was well tolerated, and cytopenias were managed using growth factors. Fifteen of 19 patients, including five of six achieving PR, had previously received irinotecan. The estimated ORR at the RP2D was 23% (lower boundary one-sided 90% CI, 9%), exceeding the unpromising rate of 5%. In addition, three patients with DSRCT had a PR at doses other than the RP2D, bringing the ORR for all doses (n = 19) to 32% (90% CI, 15% to 53%). The median overall survival was 19 months (95% CI, 13 to 36).</p><p><strong>Conclusion: </strong>The RP2D of ACR-368 with irinotecan by age group is ACR-368 105 or 150 mg/m² once on day 1 (>21 years or ≤21 years, respectively) and irinotecan 15 mg/m² once daily for 5 days in 21-day cycles for both groups. The study met its primary objective to consider ACR-368 and irinotecan promising in DSRCT and, to our knowledge, is the first incorporating a targeted therapy to achieve this magnitude of response.</p>","PeriodicalId":520350,"journal":{"name":"JCO oncology advances","volume":"2 1","pages":"e2400095"},"PeriodicalIF":0.0,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12052087/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144059727","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phase II Study of Pexidartinib Plus Sirolimus in Unresectable Malignant Peripheral Nerve Sheath Tumors Identifies M2 Macrophage Activation.","authors":"Gulam A Manji, Liam J Stanton, Angela C Hirbe, Liner Ge, Sarah Sta Ana, Shiny Titus, Brian W Labadie, Michael S May, Yang Lyu, John S A Chrisinger, Naomi Sender, Varun Monga, Mohammed Milhem, Rashmi Chugh, Peter Sims, Aik Choon Tan, Shing Lee, Brian A Van Tine, Gary K Schwartz","doi":"10.1200/OA-24-00083","DOIUrl":"https://doi.org/10.1200/OA-24-00083","url":null,"abstract":"<p><strong>Purpose: </strong>To evaluate the preliminary efficacy and safety of the combination of pexidartinib, an inhibitor of colony-stimulating factor-1 receptor (CSF1R), and sirolimus, a mammalian target of rapamycin inhibitor, to target infiltrating M2 macrophages in malignant peripheral nerve sheath tumors (MPNSTs).</p><p><strong>Patients and methods: </strong>This investigator-initiated, phase II, multicenter, single-arm trial enrolled patients with unresectable MPNSTs. Patients were treated with pexidartinib 1000 mg and sirolimus 2 mg orally daily. The primary end point was progression-free survival (PFS). Secondary end points included objective response, safety profile, and overall survival (OS). Pretreatment and on-treatment tumor biopsies were obtained to evaluate changes in the tumor microenvironment (TME) using multiplex immunofluorescence and differential transcriptional profiling.</p><p><strong>Results: </strong>Fifteen patients with MPNSTs were enrolled and 14 initiated therapy. Eight had neurofibromatosis type 1, five were sporadic, and one was undetermined. Although the target sample size was 25, because of the lower-than-expected accrual during the COVID-19 pandemic, enrollment was halted on April 12, 2023. The median PFS and median OS were 6 weeks (95% CI, 6 to 19.1) and 17.9 weeks (95% CI, 13.7 to not applicable), respectively. One patient achieved confirmed stable disease. Three patients experienced PFS ≥12 weeks. Grade 3 treatment-related toxicities (rash and leukopenia) occurred in four (28.6%) patients. Although the study did not meet its primary end point, correlative analysis demonstrated that four of the five long-term survivors had an immune-rich pretreatment TME, three of whom had a reduction in M2-tumor-associated macrophage signal with treatment.</p><p><strong>Conclusion: </strong>Further studies of combination of pexidartinib and sirolimus and/or immunotherapy should be performed in the subset of patients with advanced MPNST with an immune-rich TME.</p>","PeriodicalId":520350,"journal":{"name":"JCO oncology advances","volume":"2 1","pages":"e2400083"},"PeriodicalIF":0.0,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12053409/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144061473","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}