First results from the phase 3 CheckMate 274 trial of adjuvant nivolumab vs placebo in patients who underwent radical surgery for high-risk muscle-invasive urothelial carcinoma (MIUC).

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 391-391
Author(s):  
Dean F. Bajorin ◽  
Johannes Alfred Witjes ◽  
Jürgen Gschwend ◽  
Michael Schenker ◽  
Begoña P. Valderrama ◽  
...  
Keyword(s):  
High Risk ◽  
Residual Disease ◽  
Radical Surgery ◽  
Unmet Need ◽  
Disease Free Survival ◽  
Phase 3 ◽  
Double Blind ◽  
Meaningful Improvement ◽  
Free Survival ◽  
Disease Free

391 Background: The standard of care (SOC) for patients (pts) with MIUC is radical surgery ± cisplatin-based neoadjuvant chemotherapy (chemo), but many pts are cisplatin-ineligible. There is no conclusive evidence supporting adjuvant chemo in pts who did not receive neoadjuvant chemo and in those with residual disease after neoadjuvant cisplatin. This phase 3 trial of adjuvant nivolumab (NIVO) vs placebo (PBO) in pts with MIUC after radical surgery ± neoadjuvant cisplatin (CheckMate 274) aims to address an unmet need in these pts. We report the initial results. Methods: This is a phase 3, randomized, double-blind, multicenter trial of NIVO vs PBO in pts with high-risk MIUC (bladder, ureter, or renal pelvis) after radical surgery. Pts were randomized 1:1 to NIVO 240 mg Q2W or PBO for ≤ 1 year of adjuvant treatment. Pts had radical surgery within 120 days ± neoadjuvant cisplatin or were ineligible/declined cisplatin-based chemo, evidence of UC at high risk of recurrence per pathologic staging, were disease-free by imaging, and ECOG PS ≤ 1. Primary endpoints: disease-free survival (DFS) in all randomized pts (ITT population) and in pts with tumor PD-L1 expression ≥ 1%. DFS was stratified by nodal status, prior neoadjuvant cisplatin, and PD-L1 status. Non–urothelial tract recurrence-free survival (NUTRFS) in ITT pts and in pts with PD-L ≥ 1% is a secondary endpoint. Safety is an exploratory endpoint. Results: In total, 353 pts were randomized to NIVO (PD-L1 ≥ 1%, n = 140) and 356 pts to PBO (PD-L1 ≥ 1%, n = 142). The primary endpoint of DFS was met in ITT pts (median follow-up, 20.9 mo for NIVO; 19.5 mo for PBO) and in pts with PD-L1 ≥ 1%. DFS and NUTRFS were improved with NIVO vs PBO in both populations (Table). DFS improvement with NIVO was generally consistent across subgroups. Grade 3–4 treatment-related adverse events (TRAEs) occurred in 17.9% and 7.2% of pts in the NIVO and PBO arms, respectively. Conclusions: NIVO demonstrated a statistically significant and clinically meaningful improvement in DFS vs PBO for MIUC after radical surgery, both in ITT pts and pts with PD-L1 ≥ 1%. AEs were manageable and consistent with previous reports. These results support adjuvant NIVO as a new SOC for pts with MIUC with high risk for recurrence despite neoadjuvant chemo or those ineligible for and/or declining cisplatin-based chemo. Clinical trial information: NCT02632409 . Research Sponsor: Bristol Myers Squibb[Table: see text]

Computational features of tumor-infiltrating lymphocyte architecture of residual disease after chemotherapy on H&E images as prognostic of overall and disease-free survival for triple-negative breast cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 584-584
Author(s):  
Germán Corredor ◽  
Paula Toro ◽  
Cheng Lu ◽  
Pingfu Fu ◽  
Shaveta Vinayak ◽  
...  
Keyword(s):  
High Risk ◽  
Triple Negative ◽  
Residual Disease ◽  
Disease Free Survival ◽  
Spatial Arrangement ◽  
Training Set ◽  
Free Survival ◽  
Model Based ◽  
Spatial Architecture ◽  
Disease Free

584 Background: Approximately 30% of all breast cancers are characterized as triple-negative (TNBC). TNBC typically occurs in younger women and is associated with a poorer prognosis relative to other breast cancer subtypes. High levels of tumor-infiltrating lymphocytes (TILs) in residual disease after Neoadjuvant chemotherapy (NACT) have previously been shown to be associated with better prognosis in TNBC. In this work, we sought to evaluate the prognostic value of computationally derived measures of TIL spatial architecture in residual TNBC after NACT. Methods: H&E-stained samples from 92 patients (pts) with TNBC (41 died, 45 had disease recurrence) and residual disease after NACT were retrospectively collected from 2 sites: Instituto Nacional de Enfermedades Neoplásicas (S1) and University Hospitals (S2). 45 pts (16 deaths, 23 recurrences) from S1 formed the training set and 47 pts (25 deaths, 22 recurrences) from S2 formed the independent validation cohort. Samples were digitized at 20x. Computerized algorithms automatically identified 2 types of nuclei (TILs and non-TILs) and built clusters for each nuclei type based on cell proximity. The spatial arrangement of these clusters was then quantified using network graph metrics. The top 5 features, determined by least absolute shrinkage and selection operator, were used to train a Cox regression model that assigned a risk of death and recurrence to each patient on the training set. The percentile 33 risk score was used as a threshold for stratifying pts on the validation set as either low or high risk. For comparison, we also employed a model based on TIL density alone. Survival analysis was used to evaluate the performance of both approaches on disease-free survival (DFS) and overall survival (OS). Results: Pts in S2 (n=47) identified as “high risk” by the model based on spatial architecture of residual TILs had a significantly shorter survival time. The median OS for pts at high risk was 25 months vs. 55 months for low-risk pts. The median DFS for pts at high risk was 32 months vs 51 months for low-risk pts. Univariable analysis showed this model was prognostic for both OS (Hazard Ratio (HR) = 2.57, 95% Confidence Interval (CI): 1.07-6.16, p=0.03) and DFS (HR=2.38, CI: 1.01-5.62, p=0.04). In contrast, the model based on TIL density was not prognostic for OS (HR=1.24, CI: 0.33-4.63, p=0.73) nor DFS (HR=1.19, CI: 0.32-4.34, p=0.78). Conclusions: A computerized image analysis model based on measurements of spatial arrangement of residual TILs and surrounding cells was found to be prognostic in TNBC pts who received NACT. This method appears to be more prognostic than TIL density alone. Additional multisite validation and multivariable analysis is needed to further establish the independent prognostic utility of TIL based image biomarkers in the post-NACT TNBC.

Presence of Residual Disease Detected by Multidimensional Flow Cytometry Identifies Patients with AML At High Risk of Relapse – a Report From the Children's Oncology Group,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3545-3545 ◽  
Author(s):  
Michael R. Loken ◽  
Todd A. Alonzo ◽  
Laura Pardo ◽  
Robert B. Gerbing ◽  
Richard Aplenc ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
High Risk ◽  
Residual Disease ◽  
Disease Free Survival ◽  
Phase Iii ◽  
Advisory Committees ◽  
Free Survival ◽  
Post Induction ◽  
Risk Patients ◽  
Disease Free

Abstract Abstract 3545 We previously demonstrated that presence of post induction residual disease detected by multidimensional flow cytometry (MDF) was associated with higher relapse risk and worse survival in a cohort of 225 children treated on AAML03p1. In this study we used a similar methodology in examining the post induction marrow specimens in patients treated on the COG AML phase III trial AAML0531. This study randomized 1022 children and young adults without Down Syndrome (DS) to an MRC based chemotherapy backbone with or without Gemtuzumab Ozogamicin (GO) in the first and fourth course of therapy. Of the 1022 eligible patients, 784 patients consented to participate in the correlative biology study and submitted marrow specimens by the end of first course for evaluation of disease status by MDF. Of these 784 marrow specimens, residual disease (RD) defined as ≥0.1% blasts by MDF was identified in 240 patients (31%). Prevalence of RD in patients in morphologic CR was 20% vs. 63% in those who failed to achieve a morphologic CR (37% of those who were not in morphologic CR had no RD by MDF). Presence of RD varied by risk groups, where those with favorable risk features (CBF AML) had an RD prevalence of 14%, high risk patients (-7, -5/del5q, high risk FLT3/ITD, course 1 blasts >15%) had an RD prevalence of 68% and the intermediate risk patients had an RD prevalence of 27%. Patients with RD who were in morphologic CR or PR at the end of the first course had disease-free survival (DFS) at 3 years of 34% vs. 60% in those without RD (p<0.0001). Corresponding overall survival (OS) at 3 years was 54% and 76% in those with and without RD, respectively (p<0.0001). We further evaluated the ability of post induction RD to predict outcome in specific risk categories. Of the 180 patients considered favorable risk by cytogenetic features who were in morphologic CR or PR at end of first course, 23 had RD by MDF (13%). Presence of RD in this favorable risk cohort was not associated with worse disease-free survival (DFS, p=0.54). Similar lack of prognostic significance was observed in patients considered high risk (p=0.38). In contrast to high and low risk patients, in 435 patients with no known risk features (intermediate risk) 118 patients had RD detected by MDF (27%). DFS at 3 years from end of first course in patients with RD was 33% vs. 55% for those without RD (p<0.0001). Corresponding OS at 3 years for those with and without RD was 51% and 70%, respectively (p<0.001). This study demonstrates the significance of early response to chemotherapy as measured by MDF in predicting clinical outcome in childhood AML. It also demonstrates that the presence of RD may not be predictive of outcome in those with high or low risk features. Multi-dimensional flow cytometry has been incorporated into the current COG phase III AML trial. Disclosures: Smith: Eisai: ; Archimedes Pharma: Membership on an entity's Board of Directors or advisory committees; Pfizer, Inc.: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics:.

Phase III postneoadjuvant study evaluating sacituzumab govitecan, an antibody drug conjugate in primary HER2-negative breast cancer patients with high relapse risk after standard neoadjuvant treatment: SASCIA.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS602-TPS602
Author(s):  
Frederik Marmé ◽  
Elmar Stickeler ◽  
Jenny Furlanetto ◽  
Carsten Denkert ◽  
Marcus Schmidt ◽  
...  
Keyword(s):  
Breast Cancer ◽  
High Risk ◽  
Residual Disease ◽  
Disease Free Survival ◽  
Invasive Disease ◽  
Phase Iii ◽  
Nodal Involvement ◽  
Free Survival ◽  
Risk Of Recurrence ◽  
Disease Free

TPS602 Background: Women with triple-negative breast cancer (TNBC) having residual disease after neoadjuvant chemotherapy (NACT) as well as HR-positive/HER2-negative breast cancer (BC) with a CPS (clinical and post treatment pathological stage) +EG (estrogen receptor status and grade) score ≥ 3 or score 2 and nodal involvement after NACT (ypN+) are at high risk of recurrence. Sacituzumab govitecan is approved for the treatment of patients with metastatic TNBC who received at least two prior therapies for metastatic disease and has shown activity in heavily pretreated patients with metastatic HR-positive/HER2-negative BC. Therefore, sacituzumab govitecan may represent a new option against the resistant residual disease after standard NACT. Methods: SASCIA is a phase III, prospective, international, multi-center, randomized, open label, parallel group study in patients with HER2-negative BC with residual disease after NACT (NCT04595565). Eligible patients must have received taxane-based NACT for 16 weeks, including at least 6 weeks of a taxane. Patients should be at high risk of recurrence after treatment, defined as having centrally confirmed HER2-negative BC (IHC score 0-1 or FISH negative according to ASCO/CAP guideline) assessed preferably on tissue from postneoadjuvant residual invasive disease of the breast and either HR-negative (<1% positive stained cells), with any residual invasive disease > ypT1mi after NACT or HR-positive (≥1% positive stained cells), with a CPS+EG score ≥ 3 or CPS+EG score 2 and ypN+ using local ER and grade assessed on core biopsies taken before NACT. Radiotherapy should be delivered before the start of study treatment. Patients are randomized 1:1 to receive either sacituzumab govitecan 10 mg/kg body weight (days 1, 8 q3w for eight cycles) or treatment of physician´s choice (capecitabine 2000 mg/m² day 1-14 q21 or platinum-based chemotherapy i.e. carboplatin AUC 5 q3w or AUC 1.5 weekly for eight 3 weekly cycles or observation). Randomization is stratified by HR status (HR-positive vs negative) and nodal involvement after NACT (ypN+ vs ypN0). In patients with HR-positive BC, endocrine-based therapy will be administered according to local guidelines. The primary endpoint is invasive disease-free survival (iDFS). Secondary endpoints include comparison of overall survival (OS, key secondary endpoint), distant disease-free survival, locoregional recurrences-free interval, safety, compliance, iDFS and OS according to stratified and - predefined subgroups, patient reported outcome, and quality of life between treatment arms. As of February 2 2021, 7/1200 patients have been randomized in Germany. International study groups will join soon. Clinical trial information: NCT04595565.

scholarly journals Circulating tumor DNA as a prognostic marker in high-risk endometrial cancer

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Weiwei Feng ◽  
Nan Jia ◽  
Haining Jiao ◽  
Jun Chen ◽  
Yan Chen ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
High Risk ◽  
Tumor Recurrence ◽  
Disease Free Survival ◽  
Circulating Tumor Dna ◽  
Plasma Samples ◽  
Free Survival ◽  
Tumor Relapse ◽  
Disease Free ◽  
Tumor Dna

Abstract Background Currently, there is no reliable blood-based marker to track tumor recurrence in endometrial cancer (EC) patients. Liquid biopsies, specifically, circulating tumor DNA (ctDNA) analysis emerged as a way to monitor tumor metastasis. The objective of this study was to examine the feasibility of ctDNA in recurrence surveillance and prognostic evaluation of high-risk EC. Methods Tumor tissues from nine high-risk EC patients were collected during primary surgery and tumor DNA was subjected to next generation sequencing to obtain the initial mutation spectrum using a 78 cancer-associated gene panel. Baseline and serial post-operative plasma samples were collected and droplet digital PCR (ddPCR) assays for patient-specific mutations were developed to track the mutations in the ctDNA in serial plasma samples. Log-rank test was used to assess the association between detection of ctDNA before or after surgery and disease-free survival. Results Somatic mutations were identified in all of the cases. The most frequent mutated genes were PTEN, FAT4, ARID1A, TP53, ZFHX3, ATM, and FBXW7. For each patient, personalized ddPCR assays were designed for one-to-three high-frequent mutations. DdPCR analysis and tumor panel sequencing had a high level of agreement in the assessment of the mutant allele fractions in baseline tumor tissue DNA. CtDNA was detected in 67% (6 of 9) of baseline plasma samples, which was not predictive of disease-free survival (DFS). CtDNA was detected in serial post-operative plasma samples (ctDNA tracking) of 44% (4 of 9) of the patients, which predicted tumor relapse. The DFS was a median of 9 months (ctDNA detected) versus median DFS undefined (ctDNA not detected), with a hazard ratio of 17.43 (95% CI, 1.616–188.3). The sensitivity of post-operative ctDNA detection in estimating tumor relapse was 100% and specificity was 83.3%, which was superior to CA125 or HE4. Conclusions Personalized ctDNA detection was effective and stable for high-risk EC. CtDNA tracking in post-operative plasma is valuable for predicting tumor recurrence.

scholarly journals 300 Final analysis of a prospective, randomized, double-blind, placebo-controlled phase IIb trial of tumor lysate, particle-loaded, dendritic cell vaccine in stage III/IV melanoma: 36-month analysis

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A327-A327
Author(s):  
Lexy Adams ◽  
Robert Chick ◽  
Guy Clifton ◽  
Timothy Vreeland ◽  
Patrick McCarthy ◽  
...  
Keyword(s):  
Disease Free Survival ◽  
Stage Iv ◽  
Standard Of Care ◽  
Stage Iii ◽  
Tumor Lysate ◽  
Double Blind ◽  
Free Survival ◽  
Resected Stage ◽  
Disease Free ◽  
Stage Iv Melanoma

BackgroundThe tumor lysate, particle-loaded, dendritic cell (TLPLDC) vaccine is created ex vivo by loading autologous dendritic cells (DC) with yeast cell wall particles (YCWP) containing autologous tumor lysate, thus delivering tumor antigens to the DC cytoplasm via phagocytosis. TLPLDC then activates a robust T cell response against the unique antigens for each patient. The primary analysis of the prospective, randomized, multi-center, double-blind, placebo-controlled phase IIb trial in patients with resected stage III/IV melanoma showed TLPLDC improved 24-month disease-free survival (DFS) in the per-treatment (PT) analysis (patients completing the 6-month primary vaccine series). Here, we examine the secondary endpoint of 36-month DFS and overall survival (OS).MethodsPatients with resected stage III/IV melanoma were randomized 2:1 to TLPLDC vaccine or placebo (autologous DC loaded with empty YCWP). Treatments were given at 0, 1, 2, 6, 12 and 18 months. The protocol was amended to include patients receiving concurrent checkpoint inhibitors (CPIs) to follow changes in standard of care. The co-primary endpoints were 24-month DFS by intention-to-treat (IT) analysis and per-treatment (PT) analysis, with secondary endpoints including 36-month DFS and OS by ITT and PT analysis, pre-specified analysis by stage, and safety as measured by CTCAE v4.03.ResultsOverall, 103 patients received TLPLDC and 41 placebo. In PT analysis, 65 patients received TLPLDC and 32 placebo. Total adverse events (AEs), grade 3+ AEs, and serious AEs (SAEs) were similar in placebo vs TLPLDC groups, with one related SAE per treatment arm. By ITT analysis, 36-month OS was 76.2% for TLPLDC vs 70.3% for placebo (HR 0.72, p=0.437) and 36-month DFS was 35.6% vs 27.1% (HR 0.95, p=0.841). By PT analysis, 36-month DFS was improved with TLPLDC (57.5% vs 35.0%; HR 0.50, p=0.025, figure 1). This effect was even more dramatic in resected stage IV patients (36-month DFS: 60.9% vs 0%; HR 0.12, p=0.001, figure 2).ConclusionsThis phase IIb trial again demonstrates the safety of the TLPLDC vaccine, and an improved 36-month DFS in patients with resected stage III/IV melanoma who complete the primary vaccine series, particularly in the stage IV subgroup. Next, a phase III trial will evaluate the efficacy of TLPLDC vaccine as adjuvant treatment for resected stage IV melanoma, with patients randomized to receive standard of care PD-1 inhibitors + TLPLDC versus PD-1 inhibitors + placebo.Abstract 300 Figure 136-month disease free survival for patients receiving TLPLDC vs placebo by PT analysisAbstract 300 Figure 236-month disease free survival for subset of stage IV melanoma patients receiving TLPLDC vs placebo by PT analysisTrial RegistrationThis is a phase IIb clinical trial registered under NCT02301611Ethics ApprovalThis study was approved by Western IRB, protocol 20141932.

scholarly journals Adjuvant Gemcitabine-Oxaliplatin (GeMOX) after Curative Surgery in High-risk Patients with Cholangiocarcinoma

2009 ◽  
Vol 3 ◽  
pp. CMO.S3360
Author(s):  
Bernard Paule ◽  
Paola Andreani ◽  
Marie-Pierre Bralet ◽  
Catherine Guettier ◽  
René Adam ◽  
...  
Keyword(s):  
Survival Rate ◽  
High Risk ◽  
Adjuvant Chemotherapy ◽  
Disease Free Survival ◽  
Curative Surgery ◽  
Free Survival ◽  
High Risk Factors ◽  
Risk Patients ◽  
Disease Free Survival Rate ◽  
Disease Free

Background There is no standard adjuvant chemotherapy to prevent recurrent cholangiocarcinoma (CCA), a rare cancer with poor prognosis. We assessed the efficacy and safety of GEMOX on intrahepatic and hilar CCA with high-risk factors after curative surgery. Patients and Methods Twenty two patients (mean age: 57 years old) with CCA received 6 cycles of GEMOX: gemcitabine 1,000 mg/m2 on day 1 and oxaliplatin 85 mg/m2 on day 2, q3w after a curative surgery. Results All patients completed 6 cycles of GEMOX. EGFR membranous expression was present in 20 CCA. The 5-year survival rate was 56% (CI 95%: 25.7–85.4); 2-year disease free survival rate was 28% (CI 95%: 3.4–52.6). Median time to progression was 15 months. The rate of recurrence after surgery and chemotherapy was 63% (14/22). Two patients died of disease progression. Twelve patients received cetuximab/GEMOX at the time of relapse. Six died after 12 months (9–48 months), three are still alive suggesting a clinical applicability of EGFR inhibitors in CCA. Conclusion Adjuvant chemotherapy with GEMOX alone seems ineffective in intrahepatic and hilar CCA with a high risk of relapse. Additional studies including targeted therapies to circumvent such poor chemosensitivity are needed.

scholarly journals Primary anorectal melanoma: a case of 5 year disease-free survival

2017 ◽  
Vol 4 (2) ◽  
pp. 768
Author(s):  
Monica Urbani ◽  
Marina Troian ◽  
Gabriele Bellio ◽  
Marina Bortul
Keyword(s):  
Radical Surgery ◽  
Disease Free Survival ◽  
White Female ◽  
Anal Pain ◽  
Anorectal Melanoma ◽  
Perianal Area ◽  
Free Survival ◽  
Tailored Treatment ◽  
Inguinal Lymphadenectomy ◽  
Disease Free

Anorectal melanoma is a rare cause of anorectal malignancies affecting mainly elderly people without significant gender differences, although there seems to be a white predominance. Diagnosis is often challenging, since symptoms are frequently nonspecific. Radical surgery is the mainstay of treatment, while adjuvant therapies are generally of limited value. Thus, prognosis is still grim, with a 5-year survival rate of less than 20%. We report the case of a 75-year-old white female presenting with mild anal pain and blood in stools. Diagnosed with an ulcerated melanoma of the perianal area, she eventually underwent an abdominoperineal resection and bilateral inguinal lymphadenectomy. To date, she is currently alive and disease-free. Given the lack of adequate international guidelines, we recommend defining a tailored treatment by thorough multidisciplinary discussion, as well as taking into account the patient personal preference.

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