ESMO Open最新文献

{"title":"Efficacy and safety of the combination of encorafenib/cetuximab with or without binimetinib in patients with BRAF V600E-mutated metastatic colorectal cancer: an AGEO real-world multicenter study","authors":"","doi":"10.1016/j.esmoop.2024.103696","DOIUrl":"10.1016/j.esmoop.2024.103696","url":null,"abstract":"<div><h3>Background</h3><p>The combination of encorafenib with cetuximab has become the standard of care in patients with <em>BRAF</em> V600E-mutated metastatic colorectal cancer (mCRC) after a prior systemic therapy. This study aims to describe the efficacy and safety of encorafenib/cetuximab +/− binimetinib in patients with <em>BRAF</em> V600E-mutated mCRC in a real-world setting.</p></div><div><h3>Patients and methods</h3><p>This retrospective study included patients with <em>BRAF</em> V600E-mutated mCRC who received this combination from January 2020 to June 2022 in 30 centers.</p></div><div><h3>Results</h3><p>A total of 201 patients were included, with 55% of women, a median age of 62 years, and an Eastern Cooperative Oncology Group performance status (ECOG-PS) &gt;1 in 20% of cases. The main tumor characteristics were 60% of right-sided primary tumor, 11% of microsatellite instability/mismatch repair deficient phenotype, and liver and peritoneum being the two main metastatic sites (57% and 51%). Encorafenib/cetuximab +/− binimetinib was prescribed in the first, second, third, and beyond third line in 4%, 56%, 29%, and 11%, respectively, of cases, with the encorafenib/cetuximab/binimetinib combination for 21 patients (10%). With encorafenib/cetuximab treatment, 21% of patients experienced grade ≥3 adverse events (AEs), with each type of grade ≥3 AE observed in &lt;5% of patients. The objective response rate was 32.2% and the disease control rate (DCR) was 71.2%. The median progression-free survival (PFS) was 4.5 months [95% confidence interval (CI) 3.9-5.4 months] and the median overall survival (OS) was 9.2 months (95% CI 7.8-10.8 months). In multivariable analysis, factors associated with a shorter PFS were synchronous metastases [hazard ratio (HR) 1.66, <em>P</em> = 0.04] and ECOG-PS &gt;1 (HR 1.88, <em>P</em> = 0.007), and those associated with a shorter OS were the same factors (HR 1.71, <em>P</em> = 0.03 and HR 2.36, <em>P</em> &lt; 0.001, respectively) in addition to treatment beyond the second line (HR 1.74, <em>P</em> = 0.003) and high carcinoembryonic antigen level (HR 1.72, <em>P</em> = 0.003).</p></div><div><h3>Conclusion</h3><p>This real-world study showed that in patients with <em>BRAF</em> V600E-mutated mCRC treated with encorafenib/cetuximab +/− binimetinib, efficacy and safety data confirm those reported in the BEACON registration trial. The main poor prognostic factors for this treatment are synchronous metastases and ECOG-PS &gt;1.</p></div>","PeriodicalId":11877,"journal":{"name":"ESMO Open","volume":null,"pages":null},"PeriodicalIF":7.1,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2059702924014650/pdfft?md5=09f9d9ed9ab78316a64c0268fc0957a0&pid=1-s2.0-S2059702924014650-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142163442","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Germline BRCA pathogenic variants in patients with ovarian cancer and post-poly (ADP-ribose) polymerase inhibitor myeloid neoplasms","authors":"","doi":"10.1016/j.esmoop.2024.103685","DOIUrl":"10.1016/j.esmoop.2024.103685","url":null,"abstract":"<div><h3>Background</h3><p>Among patients with advanced high-grade ovarian carcinoma (aHGOC) treated with poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis), the presence of a germline <em>BRCA</em> pathogenic variant (g<em>BRCA</em>-PV) may increase the risk of bone marrow mutagenesis resulting in postcytotoxic therapy myelodysplastic neoplasms (MDS-pCT) or acute myeloid leukemia (AML-pCT), as it is expressed in heterozygosity also by hematopoietic progenitors. We aimed to investigate the occurrence of post-PARPi MDSs/AMLs-pCTs according to g<em>BRCA</em>-PV status.</p></div><div><h3>Patients and methods</h3><p>We conducted a retrospective single-center study to evaluate MDS/AML-pCT in patients with aHGOC and a known g<em>BRCA</em>-PV status receiving at least 8 weeks of maintenance PARPi, in any line of therapy, from February 2017 to December 2022. The endpoint was the proportion of patients who experienced MDSs-pCT and AMLs-pCT during and after treatment with PARPi, in g<em>BRCA</em>-PV carriers and non-carriers.</p></div><div><h3>Results</h3><p>A total of 166 patients were included: 95 (57%) had a g<em>BRCA</em>-PV and 72% received PARPi for recurrent disease. The number of lines of chemotherapies before and after PARPi, median overall survival, and median follow-up were comparable between g<em>BRCA</em>-PV carriers and non-carriers. After a median follow-up of 40.0 (95% confidence interval: 35.7-44.3) months, 10 (6%) patients were diagnosed with an MDS-pCT and 4 (2%) with an AML-pCT. A higher proportion of MDSs/AMLs-pCT (10% versus 2%; <em>P</em> = 0.16) and, in particular, of MDSs-pCT (9% versus 1%; <em>P</em> = 0.04) was observed among g<em>BRCA</em>-PV carriers.</p></div><div><h3>Conclusions</h3><p>The presence of a g<em>BRCA</em>-PV is associated with a higher risk of MDS-pCT and possibly of myeloid neoplasms after PARPi in patients with aHGOC who received PARPi, especially in the setting of recurrent disease.</p></div>","PeriodicalId":11877,"journal":{"name":"ESMO Open","volume":null,"pages":null},"PeriodicalIF":7.1,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2059702924014546/pdfft?md5=3fb770777641faffb73677df47c34374&pid=1-s2.0-S2059702924014546-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142094891","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Systemic anticancer therapy near the end of life: an analysis of factors influencing treatment in advanced tumor disease","authors":"","doi":"10.1016/j.esmoop.2024.103683","DOIUrl":"10.1016/j.esmoop.2024.103683","url":null,"abstract":"<div><h3>Background</h3><p>Systemic anticancer treatment (SACT) for advanced cancer patients with limited prognosis before death is associated with high toxicity and reduced quality of life. Guidelines discourage this approach as low-value care. However, a significant number of patients continue to receive SACT in the last 30 days of life.</p></div><div><h3>Materials and methods</h3><p>A retrospective study was carried out at the University Hospital Krems, encompassing the analysis of patients who were diagnosed with a solid tumor and died between 2017 and 2021, with a particular focus on the use of end-of-life (EOL) SACT.</p></div><div><h3>Results</h3><p>A total of 685 patients were included in the study. SACT was applied in 342 (49.9%) patients, of whom 143 (41.8%, total population: 20.9%) patients received SACT within the last 30 days of life. Median time from last SACT to death was 44.5 days. The analysis of potential factors impacting the administration of EOL SACT revealed the following significant findings: type of SACT [<em>P</em> &lt; 0.001, targeted therapy odds ratio (OR) 5.09, 95% confidence interval (CI) 2.26-11.48; chemotherapy/targeted therapy OR 3.60, 95% CI 1.47-8.82; immune checkpoint inhibitor OR 2.32, 95% CI 1.37-3.92], no referral to palliative care (PC) (<em>P</em> = 0.009, OR 1.86, 95% CI 1.16-2.96), no admission to PC ward (<em>P</em> &lt; 0.001, OR 2.70, 95% CI 1.67-4.35), and poor Eastern Cooperative Oncology Group (ECOG) performance status (≥2, <em>P</em> &lt; 0.001, OR 3.35, 95% CI 1.93-5.83).</p></div><div><h3>Conclusion</h3><p>The timing of SACT near the EOL is significantly influenced by several factors, including the type of SACT, referral to PC services, admission to PC unit, and ECOG performance status. These findings underscore the complexity of treatment decisions in advanced cancer care and highlight the need for personalized, patient-centered approaches that consider both clinical and patient-related factors to optimize care at the EOL.</p></div>","PeriodicalId":11877,"journal":{"name":"ESMO Open","volume":null,"pages":null},"PeriodicalIF":7.1,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2059702924014522/pdfft?md5=cbe7585044e4518e81746bb243587cbc&pid=1-s2.0-S2059702924014522-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142094724","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Efficacy of chemotherapy after progression during or following PARPi exposure in ovarian cancer☆","authors":"","doi":"10.1016/j.esmoop.2024.103694","DOIUrl":"10.1016/j.esmoop.2024.103694","url":null,"abstract":"<div><h3>Background</h3><p>Poly(ADP-ribose) polymerase inhibitors (PARPis) improved advanced ovarian cancer treatment. Most patients progress during or following PARPi exposure, however, with concerns about sensitivity of subsequent chemotherapy.</p></div><div><h3>Patients and methods</h3><p>In this international cohort study, we evaluated the efficacy of a subsequent chemotherapy following PARPi exposure in high-grade ovarian carcinoma patients. Endpoints included progression-free survival (PFS), overall survival and a multivariable Cox model was built to identify factors influencing PFS.</p></div><div><h3>Results</h3><p>We included 291 patients from four international centers treated between January 2002 and December 2021. The median number of previous chemotherapy was 1 (1.0-7.0), the median duration of PARPi exposure was 6.5 months (0.2-54.3 months). PARPi was used in first line in 14.1% patients. Most progressions occurred under PARPi exposure (89.1%). A <em>BRCA</em> pathogenic variant was identified in 130 patients (44.7%), absent in 157 patients (54.0%), and undocumented in 4 patients (1.4%). Platinum-based CT (PBC) and non-PBC were administered as subsequent treatments in, respectively, 182 patients (62.5%) and 109 patients (37.5%). Multivariable analyses showed that platinum-free interval (PFI) &gt;6 months [adjusted hazards ratio (HR), 0.52; 95% confidence interval (CI) 0.39-0.70] and type of initial surgery (adjusted HR, 1.41; 95% CI 1.07-1.87; interval or closing surgery versus primary surgery) were associated with PFS, independent of <em>BRCA</em> status or line of therapy (≥2 versus 1). In patients with a PFI &gt;6 months, PBC was numerically associated with the best PFS (adjusted HR, 0.68; 95% CI 0.46-1.01).</p></div><div><h3>Conclusion</h3><p>This is the largest real-world study assessing the efficacy of subsequent chemotherapy in patients progressing during PARPi exposure. The patients have poor outcomes. PBC is the best option in patients progressing on PARPi and eligible for PBC rechallenge (PFI &gt;6 months).</p></div>","PeriodicalId":11877,"journal":{"name":"ESMO Open","volume":null,"pages":null},"PeriodicalIF":7.1,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2059702924014637/pdfft?md5=0d38209a38e072410fb7a4f8903050ca&pid=1-s2.0-S2059702924014637-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142129922","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Induction avelumab followed by chemoimmunotherapy and maintenance versus chemotherapy alone as first-line therapy in cis-ineligible metastatic urothelial carcinoma (INDUCOMAIN): a randomized phase II study","authors":"","doi":"10.1016/j.esmoop.2024.103690","DOIUrl":"10.1016/j.esmoop.2024.103690","url":null,"abstract":"<div><h3>Background</h3><p>Platinum-based chemotherapy (ChT) has been the standard first-line treatment for metastatic urothelial carcinoma (mUC). The purpose of this study was to evaluate the use of induction avelumab followed by avelumab in combination with carboplatin-gemcitabine (carbo/gem) followed by avelumab maintenance. We tested the hypothesis that induction immunotherapy (IO) could enhance the response to ChT and prevent its detrimental effect on immune cells.</p></div><div><h3>Materials and methods</h3><p>INDUCOMAIN is a multicenter, randomized, investigator-initiated, open-label phase II study evaluating the safety and efficacy of induction avelumab before carboplatin-gemcitabine-avelumab, followed by avelumab maintenance (arm A), compared to carbo/gem (arm B). Eligibility criteria included patients with mUC, no prior systemic therapy, and ineligibility for cisplatin by Galsky criteria. Patients were stratified by the presence/absence of visceral metastasis and Eastern Cooperative Oncology Group performance status 0-1 versus 2. The primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety.</p></div><div><h3>Results</h3><p>Eighty-five patients were included and randomized to arm A (<em>n</em> = 42) and arm B (<em>n</em> = 43), respectively. ORR was similar between treatment arms: 59.5% in arm A and 53.5% in arm B (<em>P</em> = 0.57). Fourteen patients (33%) in arm A early progressed/died before or at first response assessment, compared to three patients (7%) in arm B. Median OS was 11.1 months in arm A and 13.2 months in arm B [hazard ratio (HR) 0.91, 95% confidence interval (CI) 0.57-1.46, <em>P</em> = 0.69]. Median PFS was 6.9 months in arm A versus 7.4 months in arm B (HR 0.99, 95% CI 0.61-1.60, <em>P</em> = 0.95). Treatment-related adverse events of grade 3-4 occurred in 70.7% of patients in arm A and in 72.1% in arm B. No predictive role of programmed death-ligand 1 expression was found.</p></div><div><h3>Conclusions</h3><p>The hypothesis that induction avelumab could enhance the efficacy of subsequent ChT was not proven. Administering IO alone as induction before ChT is not an adequate strategy.</p></div>","PeriodicalId":11877,"journal":{"name":"ESMO Open","volume":null,"pages":null},"PeriodicalIF":7.1,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2059702924014595/pdfft?md5=707f731783b690f86805c43ebd30e9e4&pid=1-s2.0-S2059702924014595-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142094890","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Total pain, opioids, and immune checkpoint inhibitors in the survival of patients with cancer","authors":"","doi":"10.1016/j.esmoop.2024.103688","DOIUrl":"10.1016/j.esmoop.2024.103688","url":null,"abstract":"<div><p>Experimental and observational studies have shown that opioid analgesics may increase tumor growth, potentially reduce immunotherapy efficacy, and shorten survival. As a result of the lack of clinical data, the current rationale for continuing opioid analgesic treatment is based on animal models, which suggests that physical pain itself may potentially influence cancer growth and exert immunosuppressive effects. Total pain encompasses the various factors that patients may experience during their cancer journey: physical symptoms, social isolation/loneliness, psychological, spiritual/existential, and financial distress. These need to be screened and discussed with patients to help them cope with the treatment and disease. As each issue may affect survival, it is essential to identify them to understand how they might affect the patient’s immune system, influence immunotherapy outcomes, and ultimately, survival. The question arises whether a single factor, such as the combination of opioids and immune checkpoint inhibitors, negatively affects treatment outcomes. While there is a risk of fostering opioid phobia, the complex interplay between total pain, quality of life, and the immune system must be considered. Thus, in studies that appropriately investigate the interactions between opioid analgesics and the immune system, it is essential to consider all the distress factors that patients may experience at each stage of their illness.</p></div>","PeriodicalId":11877,"journal":{"name":"ESMO Open","volume":null,"pages":null},"PeriodicalIF":7.1,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2059702924014571/pdfft?md5=9ded5b1147bd8fffcdb12c4436b6a5ef&pid=1-s2.0-S2059702924014571-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142094777","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immunotherapy in the treatment landscape of hormone receptor-positive (HR+) early breast cancer: is new data clinical practice changing?","authors":"","doi":"10.1016/j.esmoop.2024.103695","DOIUrl":"10.1016/j.esmoop.2024.103695","url":null,"abstract":"","PeriodicalId":11877,"journal":{"name":"ESMO Open","volume":null,"pages":null},"PeriodicalIF":7.1,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2059702924014649/pdfft?md5=78a3635c6fd309c1a7c21a8c6826515f&pid=1-s2.0-S2059702924014649-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142163591","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Real-world treatment patterns and outcomes in patients with HR+/HER2− metastatic breast cancer treated with chemotherapy in the United States","authors":"","doi":"10.1016/j.esmoop.2024.103691","DOIUrl":"10.1016/j.esmoop.2024.103691","url":null,"abstract":"<div><h3>Background</h3><p>Until recently, treatment options for patients with hormone receptor-positive/human epidermal growth factor 2-negative (HR+/HER2−) metastatic breast cancer (mBC) and resistance to endocrine therapy were limited to chemotherapy. This real-world study describes treatment patterns and outcomes in patients treated with chemotherapy in the United States before approval of antibody–drug conjugates.</p></div><div><h3>Patients and methods</h3><p>This retrospective, observational study included adults with HR+/HER2− mBC from the ConcertAI Patient360™ Breast Cancer dataset who initiated their first chemotherapy in the metastatic setting between January 2011 and June 2021. Treatment patterns were described; real-world overall survival, time to next treatment or death, and real-world progression-free survival were evaluated for all eligible patients and patients treated with subsequent chemotherapy. Index dates were the start date of each chemotherapy treatment.</p></div><div><h3>Results</h3><p>Among 1545 eligible patients, 76% were white, 12% had Eastern Cooperative Oncology Group performance status ≥2, 38% had <em>de novo</em> mBC, and median age was 61 years (range, 52-69 years). Within the index period, capecitabine was used the most as the first chemotherapy agent and decreased in later treatments, while the use of eribulin increased between first and fourth chemotherapies. Median (95% confidence interval) real-world overall survival was 23.3 months (21.3-25.4 months) from start of first chemotherapy, time to next treatment or death was 6.5 months (5.9-7.1 months), and real-world progression-free survival was 6.9 months (6.4-7.6 months); median times from second, third, and fourth chemotherapies decreased with each additional chemotherapy treatment.</p></div><div><h3>Conclusions</h3><p>This real-world study demonstrates that for patients with HR+/HER2− mBC, chemotherapy provides relatively limited survival benefit which decreases with each additional chemotherapy line, and highlights the need for improved treatment options.</p></div>","PeriodicalId":11877,"journal":{"name":"ESMO Open","volume":null,"pages":null},"PeriodicalIF":7.1,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2059702924014601/pdfft?md5=aa0c5958a6d46a8ef6538163a5b0765b&pid=1-s2.0-S2059702924014601-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142145419","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PF-06952229, a selective TGF-β-R1 inhibitor: preclinical development and a first-in-human, phase I, dose-escalation study in advanced solid tumors","authors":"","doi":"10.1016/j.esmoop.2024.103653","DOIUrl":"10.1016/j.esmoop.2024.103653","url":null,"abstract":"<div><h3>Background</h3><p>PF-06952229 is a selective small-molecule inhibitor of transforming growth factor-β (TGF-β) receptor 1. We evaluated its antitumor activity in preclinical studies and its safety, tolerability, pharmacokinetics, and pharmacodynamics in a phase I study (NCT03685591).</p></div><div><h3>Patients and methods</h3><p><em>In vitro</em> and <em>in vivo</em> preclinical studies were conducted. Patients (aged ≥18 years) received PF-06952229 monotherapy [20-500 mg, oral b.i.d., 7 days on/7 days off, 28-day cycles, Part 1A (P1A)] for advanced/metastatic solid tumors and combination therapy [250/375 mg with enzalutamide, Part 1B (P1B)] for metastatic castration-resistant prostate cancer (mCRPC). Primary endpoints were dose-limiting toxicity (DLT), adverse events (AEs), and laboratory abnormalities. Efficacy, pharmacokinetic parameters, and biomarker modulation were assessed.</p></div><div><h3>Results</h3><p>PF-06952229 showed activity in preclinical murine tumor models including pSMAD2 modulation in tumors. The study (NCT03685591) enrolled 49 patients (P1A, <em>n</em> = 42; P1B, <em>n</em> = 7). DLTs were reported in 3/35 (8.6%) P1A patients receiving PF-06952229 375 mg (anemia, intracranial tumor hemorrhage, and anemia and hypertension, all grade 3, <em>n</em> = 1 each). The most frequent grade 3 treatment-related AEs (TRAEs) were alanine aminotransferase increased and anemia (9.5% each). There were no grade 4-5 TRAEs. Plasma PF-06952229 exposures were dose proportional between 80 and 375 mg. Pharmacodynamic studies confirmed target modulation of pSMAD2/3 (peripheral monocytes). One P1A patient with prostate cancer receiving PF-06952229 375 mg monotherapy achieved confirmed partial response (31-month duration of response). A total of 8 patients (P1A, <em>n</em> = 6; P1B, <em>n</em> = 2) achieved stable disease.</p></div><div><h3>Conclusions</h3><p>Antitumor activity of PF-06952229 was observed in preclinical studies. PF-06952229 was generally well tolerated with manageable toxicity; a small group of patients achieved durable responses and/or disease stabilization.</p></div>","PeriodicalId":11877,"journal":{"name":"ESMO Open","volume":null,"pages":null},"PeriodicalIF":7.1,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2059702924014224/pdfft?md5=6816b1a54b511f0be06c951f70251f55&pid=1-s2.0-S2059702924014224-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142094725","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"mFOLFOX6 versus mFOLFOX6 + aflibercept as neoadjuvant treatment in MRI-defined T3-rectal cancer: a randomized phase-II-trial of the German Rectal Cancer Study Group (CAO/ARO/AIO 0214)","authors":"","doi":"10.1016/j.esmoop.2024.103703","DOIUrl":"10.1016/j.esmoop.2024.103703","url":null,"abstract":"<div><h3>Background</h3><p>Neoadjuvant chemotherapy is an option for patients with locally advanced rectal cancer at low risk for local recurrence. This randomized phase II trial investigated whether the addition of aflibercept to modified FOLFOX6 (mFOLFOX6) could improve the rates of centrally confirmed pathological complete remissions (pCR) and (disease-free) survival in magnetic resonance imaging (MRI)-staged cT3 rectal cancer.</p></div><div><h3>Patients and methods</h3><p>Patients with rectal cancer fulfilling the following criteria were included: lower border of tumor &gt;5 cm and &lt;16 cm from anal verge; circumferential resection margin &gt;2 mm and T3-tumor with a maximum infiltration of 10 mm, as determined by MRI. Patients were randomized 1 : 2 to six cycles mFOLFOX6 ± aflibercept. Surgery was scheduled 4 weeks after chemotherapy. Primary endpoint was the rate of centrally confirmed pCR. The study was designed to detect an improvement of pCR from 10% to 27% (power 80%, type I error 20%).</p></div><div><h3>Results</h3><p>A total of 119 randomized patients started treatment (39 patients mFOLFOX6, arm A, and 80 mFOLFOX + aflibercept, arm B). The incidence of all grade adverse events was similar in both arms, however, adverse events grade ≥3 were more than twice as high in the experimental arm due to hypertension. Surgical complications were comparable. Aflibercept did not improve the pCR rate (arm A 26% versus arm B 19%, <em>P</em> = 0.47) and more patients in arm B had node positivity. With a median follow-up of 40.1 months, the 4-year disease-free survival was 83% in arm A and 85% in arm B (<em>P</em> = 0.82). Only two patients in arm A and one patient in arm B developed local recurrence.</p></div><div><h3>Conclusions</h3><p>In patients with locally advanced rectal cancer and MRI-defined low risk of local recurrence, neoadjuvant mFOLFOX6 + aflibercept was feasible and did not compromise surgery. Survival data were favorable in both arms, but pCR rates were not increased by the addition of aflibercept.</p></div>","PeriodicalId":11877,"journal":{"name":"ESMO Open","volume":null,"pages":null},"PeriodicalIF":7.1,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2059702924014728/pdfft?md5=a2733c93d35cb05a1daac7ab55272d88&pid=1-s2.0-S2059702924014728-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142163443","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}