Improvement In Relapse-free Survival Research Articles

Novel RNA-nanoparticle vaccine for the treatment of early melanoma recurrence following adjuvant anti-PD-1 antibody therapy.

TPS9609 Background: Melanoma is a major public health concern with an anticipated increase in prevalence and incidence in the coming years. Early detection and surgical management remain the mainstay of treatment of early-stage disease and use of adjuvant immunotherapy has improved outcomes for patients with more aggressive (IIB-IIC) local disease or those with lymph node involvement (IIIA-IIID). Based on the tolerability and efficacy across subjects with both BRAF mutated and wildtype melanoma anti-PD1 (aPD1) therapy with either nivolumab or pembrolizumab are considered first line treatment in this setting. Adjuvant aPD1 therapy has significant improvement in relapse free survival (RFS) yet 25-30% of subjects will have disease recurrence within 1 year of surgery. When disease recurs, the response rate to immunotherapy is significantly reduced, re-challenged with aPD1 therapy has shown an Objective Response Rate (ORR) of zero and a marginally better response to CTLA-4 blockade. Novel strategies are needed for this at-risk population with early aPD1 resistance. To address this need we have developed a novel multi-lamellar lipid-nanoparticle complexed with total-tumor derived mRNA administered intravenously to restore responsiveness to aPD1 through reprogramming the tumor microenvironment (TME) bridging an innate and adaptive immune response. We have designed a clinical trial in which patients who progress on while on aPD1 therapy or within 6 months of therapy will have tumor sampled and a personalized lipid-nanoparticle vaccine generated. This vaccine is then administered IV for a total of 3 doses spanning 6 weeks to reprogram the TME and restore response to aPD1 which will be resumed on completion of vaccine series. This phase I study will assess initial feasibility and safety of vaccine generation, utilize ctDNA surveillance as early detection of adjuvant failure, and provide essential biologic information on immunotherapy resistance to aPD1 therapy. Methods: We have designed a modified 3+3 phase I clinical trial that will enroll subjects who have evidence of progressive disease (PD) by ctDNA and/or RECIST 1.1 criteria while receiving adjuvant aPD1 therapy, or those who progress within 6 months of completion of treatment for stage IIB-IIID melanoma. The goal of this study is to assess safety, tolerability, and feasibility of tumor specific RNA-LPs. Important biological correlates will also be collected and analyzed including tumor tissue sampling at initial time of checkpoint resistance and following vaccination series to identify key changes to the TME and tumor induced by lipid-nanoparticle vaccine administration. Clinical trial information: NCT05264974 .

Adjuvant S-1 vs. observation for resected biliary tract cancer: 5-year follow-up of the JCOG1202/ASCOT.

4119 Background: S-1, an oral fluoropyrimidine derivative, demonstrated significant improvement in overall survival (OS) over observation in patients with curatively resected biliary tract cancer (BTC) (hazard ratio [HR] 0.694, p=0.008; the 3-year OS, 67.6% vs. 77.1%, Lancet 2023). We present updated efficacy data based on a 5-year follow-up of JCOG1202/ASCOT. Methods: Patients aged 20-80 years who had histologically confirmed extrahepatic cholangiocarcinoma, gallbladder carcinoma, ampullary carcinoma, or intrahepatic cholangiocarcinoma in a resected specimen and had undergone R0/R1 resection were randomly assigned (1:1) to undergo observation or to receive S-1 (at the dose of 40 mg/m2 twice daily for 4 weeks, followed by 2 weeks of rest, for 4 cycles). The primary endpoint was OS, and the secondary endpoints were relapse-free survival (RFS), adverse events, and proportion of treatment completion. Results: From September 2013 to June 2018, a total of 440 patients (observation, n=222; adjuvant S-1, n=218) were enrolled. The final data cutoff date was June 23, 2023, and the median follow-up duration was 61.5 months. Of all the randomized patients, 215 (48.4%) had died (118 [53.2%] in the observation group; 97 [44.5%] in the S-1 group). The 5-year OS was 52.2% in the observation group and 64.1% in the S-1 group (stratified HR 0.723, 95% confidence interval [CI], 0.551-0.948; one-sided p=0.019). Of the 440 patients, 239 (54.3%) had RFS event (127 [57.2%] in the observation group; 112 [51.4%] in the S-1 group). The 5-year RFS was 45.9% in the observation group and 53.6% in the S-1 group (unstratified HR 0.797, 95% CI 0.618-1.028, stratified HR 0.761, 95% CI 0.589-0.984 in the sensitivity analysis). Most prespecified subgroup analyses (age, primary site, stage, lymph node metastases, types of resections, and serum CA19-9 levels) revealed favorable OS and RFS for the S-1 group. Conclusions: Adjuvant S-1 therapy maintained its survival benefit in a 5-year long-term follow-up, with clinically meaningful improvement in RFS, suggesting that it could be a standard of care for BTC. Clinical trial information: UMIN000011688.

Gilteritinib as Post-Transplant Maintenance for AML With Internal Tandem Duplication Mutation of FLT3.

Allogeneic hematopoietic cell transplantation (HCT) improves outcomes for patients with AML harboring an internal tandem duplication mutation of FLT3 (FLT3-ITD) AML. These patients are routinely treated with a FLT3 inhibitor after HCT, but there is limited evidence to support this. Accordingly, we conducted a randomized trial of post-HCT maintenance with the FLT3 inhibitor gilteritinib (ClinicalTrials.gov identifier: NCT02997202) to determine if all such patients benefit or if detection of measurable residual disease (MRD) could identify those who might benefit. Adults with FLT3-ITD AML in first remission underwent HCT and were randomly assigned to placebo or 120 mg once daily gilteritinib for 24 months after HCT. The primary end point was relapse-free survival (RFS). Secondary end points included overall survival (OS) and the effect of MRD pre- and post-HCT on RFS and OS. Three hundred fifty-six participants were randomly assigned post-HCT to receive gilteritinib or placebo. Although RFS was higher in the gilteritinib arm, the difference was not statistically significant (hazard ratio [HR], 0.679 [95% CI, 0.459 to 1.005]; two-sided P = .0518). However, 50.5% of participants had MRD detectable pre- or post-HCT, and, in a prespecified subgroup analysis, gilteritinib was beneficial in this population (HR, 0.515 [95% CI, 0.316 to 0.838]; P = .0065). Those without detectable MRD showed no benefit (HR, 1.213 [95% CI, 0.616 to 2.387]; P = .575). Although the overall improvement in RFS was not statistically significant, RFS was higher for participants with detectable FLT3-ITD MRD pre- or post-HCT who received gilteritinib treatment. To our knowledge, these data are among the first to support the effectiveness of MRD-based post-HCT therapy.

Adjuvant chemotherapy combined with immunotherapy in patients with cholangiocarcinoma after radical resection.

The malignancy of cholangiocarcinoma is highly pronounced, and it exhibits a propensity for recurrence and metastasis even in the presence of standard chemotherapy. The efficacy of adjuvant chemotherapy combined with immunotherapy in patients with resected cholangiocarcinoma needs to be substantiated. Data from 101 patients with cholangiocarcinoma treated at the Sun Yat-sen University Cancer Center between 2015 and 2020 were studied. After propensity score matching, there were no significant differences in baseline characteristics between patients in the combined adjuvant chemotherapy and immunotherapy group (AC + IM group) and the adjuvant chemotherapy alone group (AC group) (all p > 0.05). The AC + IM group demonstrated a statistically significant improvement in relapse-free survival (RFS) compared to the AC group (p = 0.032). Likewise, the AC + IM group exhibited a significantly superior overall survival (OS) outcome when compared to the AC group (p = 0.044). Multivariate Cox analysis unveiled perineural invasion (p = 0.041), lymph node metastasis (p = 0.006), and postoperative immunotherapy (p = 0.008) as independent prognostic factors exerting a significant impact on the OS of patients. In the cohort of patients with perineural invasion, the AC + IM group exhibited significantly improved OS compared to the AC group (p = 0.0077). Similarly, within the subset of patients with lymph node metastasis, the AC + IM group exhibited a significantly superior OS outcome when compared to the AC group (p = 0.023). Combining postoperative adjuvant chemotherapy with immunotherapy extends the RFS and OS of patients with cholangiocarcinoma following radical resection.

Age-Adapted Chemotherapy for Adults >40 Years Old with Philadelphia Chromosome Negative Acute Lymphoblastic Leukemia: Single Center Outcomes

Introduction: While pediatric-inspired regimens are preferred in younger adults with Ph-negative ALL, the optimal approach for treating adults age >40 with Ph-negative ALL has not yet been defined. In the U.S., hyperCVAD-based regimens are commonly used in this age group; however, hyperCVAD may be less effective than pediatric-inspired regimens in patients who are appropriate candidates for intensive therapy, and may be excessively toxic in patients who are poor candidates for intensive therapy. We explored giving two different multiagent chemotherapy regimens to adults age >40 with newly diagnosed Ph-negative ALL, depending on the individual patient's age and fitness level. Methods: At our institution starting in September 2020, patients between 40-60yo with good performance status received an intensive pediatric-inspired regimen based on the CALGB 10403 backbone, while patients >60yo (or 50-60 with poor PS) received a moderate-intensity multiagent chemotherapy backbone consisting of 2-part induction (induction-1: infusional doxorubicin/vincristine D1-4 + dexamethasone 40mg D1-4, 9-12, 17-20; induction-2: same as induction-1 plus cyclophosphamide 1000mg/m 2 on day 1) and consolidation with 6 cycles of chemotherapy, alternating between methotrexate (1g/m 2) plus peg-asparaginase (1,000U/m 2), and cytarabine (1g/m 2 x 6 doses). Prior to September 2020, patients in this age group received the hyperCVAD backbone. In both cohorts, patients not proceeding to allogeneic SCT in CR1 received POMP maintenance for up to 2 years. We reviewed charts of patients aged >40 with newly diagnosed Ph-negative ALL at University of Colorado Hospital from 2014-2023 to compare outcomes between patients treated before 09/2020 (“hyperCVAD” cohort) and after 09/2020 (“age-adapted” cohort). Results: Between 09/2020-04/2023, 17 adults with median age of 57 (range 40-81) with newly diagnosed Ph-negative ALL began treatment at our institution. 6 patients (age 40-56) received a modified pediatric-inspired regimen, and 11 patients (age 54-81) received a moderate-intensity regimen. 4 patients underwent allogeneic SCT in CR1 (including 1 for tMDS that developed during maintenance therapy). 3 patients received blinatumomab in CR1, 2 of whom subsequently received allo SCT. With a median follow-up of 16 months (range: 1-32 months), 1 patient relapsed during maintenance and 2 patients died from treatment-related mortality (1 during induction chemotherapy, 1 during salvage therapy for primary refractory disease). All three events occurred in patients who received the moderate-intensity regimen. Grade 3 or 4 asparaginase-related toxicities occurred in 2 patients (1 gr3 hyperbilirubinemia, 1 gr3 pancreatitis) and both resolved with supportive care. Between 2014-2020, 18 adults with median age of 58 (range 42-80) received hyperCVAD for newly diagnosed Ph- ALL. 6 patients received allogeneic SCT in CR1, and no patients received blinatumomab in CR1. With a median follow-up of 31 months (range: 7-94 months), 7 patients relapsed during consolidation or maintenance therapy and 3 relapsed after SCT. Among 10 patients who died during follow-up, 7 deaths were due to relapsed/refractory disease and 3 were due to treatment-related mortality (all 3 TRM were post-transplant). An improvement in relapse-free survival is seen in the cohort treated with age-adapted chemotherapy vs. the hyperCVAD cohort (p=0.045, log-rank test) (Figure 1), while there was no difference in overall survival (p=0.29) (not shown). Conclusions: Age-adapted multiagent chemotherapy is safe and effective in adults age >40 with Ph-negative ALL and may result in better outcomes than hyperCVAD. This is possibly due to better efficacy of pediatric-inspired chemotherapy for younger (40-60yo) patients and better tolerability of moderate-intensity chemotherapy for older (>60yo) patients, compared to hyperCVAD. Broad use of asparaginase in both the pediatric-inspired and moderate-intensity regimens may have also contributed to better outcomes in comparison to hyperCVAD. Incorporation of novel therapies in the frontline setting holds much promise to improve outcomes for older adults with Ph- ALL. Our observations suggest that the specific multi-agent chemotherapy regimen used, and in particular the incorporation of peg-asparaginase, may also affect outcomes significantly.

Outcomes after interruption of targeted therapy in patients with histiocytic neoplasms.

Little is known about outcomes following interruption of targeted therapy in adult patients with histiocytic neoplasms. This is an IRB-approved study of patients with histiocytic neoplasms whose BRAF and MEK inhibitors were interrupted after achieving complete or partial response by 18-fluorodeoxyglucose positron emission tomography (FDG-PET). 17/22 (77%) of patients experienced disease relapse following treatment interruption. Achieving a complete response prior to interruption, having a mutation other than BRAFV600E, and receiving MEK inhibition only were each associated with a statistically significant improvement in relapse-free survival. Relapse is common following treatment interruption however some patients may be suitable for limited-duration treatment.

Has the advent of modern adjuvant systemic therapy for melanoma rendered sentinel node biopsy unnecessary?

The prognostic value of sentinel node biopsy (SNB) is well established and SNB was therefore adopted as a requirement for pathological staging of melanomas>1 mm thick in the American Joint Committee on Cancer (AJCC) 8th edition. Consequently, a negative SNB status became an eligibility criterion for clinical trials of adjuvant systemic therapy in resected stage IIB/C melanoma. However, since the Keynote 716 trial demonstrated an improvement in relapse-free survival (RFS) in patients with Stage IIB/C melanoma, all of whom had SNB staging, some have argued that SNB is no longer required for patients with T3 and T4 primary melanomas. The rationale for omitting SNB is that these patients will be able to access adjuvant immunotherapy regardless of SNB status, avoiding the costs and potential complications of SNB. However, this argument overlooks the prognostic value of knowing a patient’s nodal status and the therapeutic benefit of SNB in regional disease control. Based on extrapolation of data from multiple sources, we demonstrate that the risk of regional node-field relapse with SNB and immunotherapy for T3b and T4 melanomas is around 7–9% but is 20–27% without SNB. Similarly, the node-field recurrence rate with SNB alone is around 14% compared to around 40% with no SNB or immunotherapy. Consequently, in the absence of prospective data, we propose that the optimal management of the regional node-field for high-risk T3b and T4 primary melanomas is likely to be achieved by combining SNB and adjuvant immunotherapy for those patients who are suitable, rather than either treatment alone.

Prognostic value of postoperative ctDNA detection in patients with early non-small cell lung cancer: a systematic review and meta-analysis.

Circulating tumor DNA (ctDNA) has emerged as a potential biomarker for monitoring early non-small cell lung cancer (ENSCLC), particularly after radical surgery. However, the prognostic value of postoperative ctDNA is still being investigated due to the small sample size and heterogeneity of patients with ENSCLC in current trials. Moreover, the potential clinical utility of ctDNA assessment for administering adjuvant therapy (AT) in patients with ENSCLC is also an important area of active research. We aimed to identify the prognostic value of postoperative ctDNA detection in ENSCLC patients with stages I-III. This study type is a systematic review and meta-analysis. We conducted a search in the Cochrane Library, Embase, PubMed, and ScienceDirect for prospective or retrospective investigations involving patients with ENSCLC, gathering outcomes based on predefined end points. The literature review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, and the Newcastle-Ottawa scale was employed to carry out a quality evaluation of the included studies. The primary end point of the study was to evaluate the association of ctDNA status in two time points (within 1 month after surgery and long-term postoperative monitoring with more than 3 months) with relapse-free survival (RFS) and overall survival (OS). In addition, the study investigated the role of ctDNA in predicting the response to AT. The secondary end points of the study were to determine the impact of ctDNA on RFS and OS in different subgroups of ENSCLC patients based on pathological subtypes and TNM staging. In total, 2149 studies were screened, and 11 studies met the inclusion criteria for the analysis. The presence of ctDNA within 1 month after surgery as well as long-term postoperative ctDNA were both associated with poorer RFS [hazard ratio (HR) = 4.43; 95% CI: 3.23-6.07 and HR = 7.99; 95% CI: 3.28-19.44, respectively] and worse OS (HR = 5.07; 95% CI: 2.80-9.19 and HR = 7.49; 95% CI: 3.42-16.43, respectively). Most subgroup analyses yielded similar results. Moreover, ctDNA-positive patients could acquire survival benefits from AT (HR = 0.30; 95% CI: 0.16-0.54), while ctDNA-negative patients that received AT did not show significant improvement in RFS (HR = 1.18; 95% CI: 0.67-2.09). The postoperative ctDNA assessment is a promising approach to stratify the risk of relapse and death in ENSCLC patients. Our data suggest that patients with negative ctDNA in the postoperative setting may not benefit from AT, which warrants further investigation. This finding, if validated in prospective trials with a larger sample size, could aid in better-individualized treatment for patients and avoid potential side effects of AT. This study was designed in accordance with PRISMA and registered with PROSPERO (CRD42022311615).

Protective effect of tertiary lymphoid structures against hepatocellular carcinoma: New findings from a genetic perspective.

BackgroundTertiary lymphoid structures (TLS) have an effect on hepatocellular carcinoma (HCC), but the underlying mechanism remains to be elucidated.MethodsIntratumoral TLS (iTLS) was classified in the Cancer Genome Atlas-Liver Hepatocellular Carcinoma (TCGA-LIHC) cohort using pathological sections from the Cancer Digital Slide Archive. Univariate and multivariate Cox regression analyses were performed to validate the effect of iTLS on overall survival (OS), relapse-free survival (RFS), and disease-free survival (DFS). The genes differentially expressed between the iTLS-negative and iTLS-positive groups were analyzed in combination with sequencing data. Gene set enrichment analysis (GSEA) was used to explore the signaling pathways affected by these differentially expressed genes. The random forest algorithm was used to identify genes with the highest correlation with the iTLS in the training set. Multivariate logistic regression was used to build a model to predict iTLS in tissue samples. Spearman’s correlation was used to analyze the relationship between TLS-associated chemokines and signature genes, and CIBERSORT was used to calculate immune infiltration scores. Copy number variation and its relationship with immune cell infiltration and signature genes were assessed using the gene set cancer analysis (GSCA). The Correlation R package was used for gene ontology (GO), disease ontology (DO), and gene mutation analyses. The GSCA was used for drug sensitivity analysis. LASSO regression was used to build prognostic models, and external data were used to validate the models.ResultsThere were 218 positive and 146 negative samples for iTLS. iTLS was significantly associated with better RFS and DFS according to Cox regression analysis. Twenty signature genes that were highly associated with iTLS positivity were identified. GO and mutation analyses revealed that the signature genes were associated with immunity. Most signature genes were sensitive to immune checkpoint inhibitors. Risk scores calculated using a characteristic gene-based prognostic model were found to be an independent prognostic factor for OS.ConclusionsThe improvement of RFS in HCC by iTLS was not limited to the early period as previously reported. iTLS improved DFS in patients. Characteristic genes are closely related to the formation of iTLS and TLS chemokines in HCC. These genes are closely related to immunity in terms of cellular infiltration, biological functions, and signaling pathways. Most are sensitive to immune checkpoint inhibitors, and their expression levels can affect prognosis.

Enhanced immune activation within the tumor microenvironment and circulation of female high-risk melanoma patients and improved survival with adjuvant CTLA4 blockade compared to males

BackgroundWe hypothesized that a gender difference in clinical response may exist to adjuvant CTLA4 blockade with ipilimumab versus high-dose IFNα (HDI). We investigated differences in candidate immune biomarkers in the circulation and tumor microenvironment (TME).Patients and methodsThis gender-based analysis was nested within the E1609 trial that tested adjuvant therapy with ipilimumab 3 mg/kg (ipi3) and 10 mg/kg (ipi10) versus HDI in high risk resected melanoma. We investigated gender differences in treatment efficacy with ipi3 and ipi10 versus HDI while adjusting for age, stage, ECOG performance (PS), ulceration, primary tumor status and lymph node number. Forest plots were created to compare overall survival (OS) and relapse free survival (RFS) between ipi and HDI. Gene expression profiling (GEP) was performed on tumors of 718 (454 male, 264 female) patients. Similarly, serum and peripheral blood mononuclear cells (PBMC) samples were tested for soluble and cellular biomarkers (N = 321 patients; 109 female and 212 male).ResultsThe subgroups of female, stage IIIC, PS = 1, ulcerated primary, in-transit metastasis demonstrated significant improvement in RFS and/or OS with ipi3 versus HDI. Female gender was significant for both OS and RFS and was further explored. In the RFS comparison, a multivariate Cox regression model including significant variables indicated a significant interaction between gender and treatment (P = 0.024). In peripheral blood, percentages of CD3+ T cells (P = 0.024) and CD3+ CD4+ helper T cells (P = 0.0001) were higher in females compared to males. Trends toward higher circulating levels of IL1β (P = 0.07) and IL6 (P = 0.06) were also found in females. Males had higher percentages of monocytes (P = 0.03) with trends toward higher percentages of regulatory T cells (T-reg). Tumor GEP analysis supported enhanced infiltration with immune cells including gammadelta T cells (P = 0.005), NK cells (P = 0.01), dendritic cells (P = 0.01), CD4+ T cells (P = 0.03), CD8+ T cells (P = 0.03) and T-reg (P = 0.008) in the tumors of females compared to males and a higher T-effector and IFNγ gene signature score (P = 0.0244).ConclusionFemale gender was associated with adjuvant CTLA4 blockade clinical benefits and female patients were more likely to have evidence of type1 immune activation within the TME and the circulation.Trial registration ClinicalTrials.gov NCT01274338. Registered 11 January 2011, https://www.clinicaltrials.gov/ct2/show/NCT01274338

Adjuvant temozolomide plus cisplatin versus high-dose interferon alpha-2b in resected mucosal melanoma: A randomized, multicenter, controlled, phase III trial.

9578 Background: Mucosal melanoma (MuM) is a rare cancer with an extremely poor prognosis and no established standard adjuvant therapy. A phase II trial showed promising outcomes with adjuvant temozolomide plus cisplatin (Chemo) versus high-dose interferon alpha-2b (HDI) in resected mucosal melanoma. We conducted the phase III trial to definitively compare these two treatments. Methods: In this multicenter, randomized, controlled, phase III trial, patients with pathologically confirmed stage I-III mucosal melanoma who had undergone complete resection were stratified by primary site (head and neck vs. non-head and neck) and disease stage (I/II vs. III) and randomized 1:1 to receive Chemo (temozolomide 200 mg/m2/day orally on days 1 to 5 plus cisplatin 75 mg/m2 i.v. on days 1-3, repeated every 3 weeks for six cycles) or HDI (15×106 U/m2/day i.v on days 1 to 5 each week for 4 weeks followed by 9×106 U three times per week for 48 weeks). Postoperative radiotherapy was recommended for head and neck MuM patients, with a total dose of 65-70 Gy/30-35 fx to GTV and 60 Gy/30 Fx to CTV. The primary endpoint was relapse-free survival (RFS). Secondary endpoints included distant metastasis-free survival (DMFS), overall survival (OS), and safety. The protocol was registered at ClinicalTrials.gov (NCT03435302). Results: Between Feb 2014 and Jun 2016, 204 patients were randomized to treatment (Chemo group: n = 103, HDI group: n = 101). Baseline characteristics were generally well balanced between the two groups. Anatomic site of head and neck, gastrointestinal, gynecological were 38.8% vs 49.5%, 35.9% vs 22.8%, 25.2% vs 27.7% in Chemo and HDI group, respectively. Stage of I/II, III were 68.9% vs 73.3%, 31.1% vs 26.7% in Chemo and HDI group, respectively. CKIT, BRAF, NRAS Mutation were 7.0% vs 8.2%, 5.0% vs 8.2%, 13.4% vs 15.8% in Chemo and HDI group, respectively. In the ITT population, At a median follow-up of 64.8 months, patients receiving Chemo had a higher median RFS (15.5 vs. 9.9 months; HR = 0.622; 95% CI, 0.463 to 0.836; P = 0.001), DMFS (19.5 vs. 12.7 months; HR = 0.705; 95% CI, 0.518 to 0.959; P = 0.025) and OS (38.2 vs. 33.5 months; HR = 0.832; 95% CI, 0.598 to 1.155; P = 0.270) versus the HDI group. A subgroup analysis revealed consistent improvements in RFS, DMFS and OS with Chemo versus HDI across multiple subgroups. Toxicities were generally mild to moderate in both groups. The most common adverse events were fatigue, anorexia, nausea/vomiting, leukopenia, Neutropenia, hepatotoxicity, fever and anemia, 23 patients (22.3%) in Chemo group and 57 patients (56.4%) in HDI group had a grade 3 or 4 adverse events. Conclusions: Adjuvant temozolomide plus cisplatin led to a significantly lower risk of relapse and distant metastasis in patients with resected mucosal melanoma versus high-dose IFN-a2b and was generally well tolerated. Clinical trial information: NCT03435302.

Individual patient data meta-analysis of adjuvant gemcitabine-based chemotherapy for biliary tract cancer: combined analysis of the BCAT and PRODIGE-12 studies

BackgroundAlthough gemcitabine-based chemotherapy is the standard of care for advanced biliary tract cancers (BTCs), adjuvant phase III studies (BCAT in Japan, PRODIGE 12 in France) failed to show benefit, possibly owing to fewer patients (n = 225 and n = 194) compared with the adjuvant capecitabine BILCAP trial (n = 447). We performed a combined analysis of both gemcitabine-based chemotherapy adjuvant studies. MethodsWe performed individual patient data meta-analysis of all patients included in BCAT and PRODIGE 12. BCAT study randomised patients with extrahepatic cholangiocarcinoma to single-agent gemcitabine or observation. PRODIGE 12 randomised patients with all BTC subtypes to gemcitabine-oxaliplatin combination or observation. Combined analysis was performed using Kaplan–Meier curves and a Cox regression model stratified on the trial. ResultsTwo hundred and twelve versus 207 patients were randomised in the gemcitabine-based chemotherapy versus observation arms. Baseline characteristics were balanced between arms. The median follow-up was 5.5 years. After 258 relapse-free survival (RFS) events, there was no difference in RFS (log-rank p = 0.45; hazard ratio [HR] = 0.91 [95% confidence interval [CI] 0.71–1.16]; p = 0.46). RFS rates at five years were 40.8% (95%CI: 33.9%–47.5%) for gemcitabine-based chemotherapy versus 36.6% (95%CI: 29.8%–43.4%) for observation. After 201 deaths, there was no difference in overall survival (OS) (log-rank p = 0.83; HR = 1.03 [95%CI: 0.78–1.35]; p = 0.85). OS rates at five years were 50.5% (95%CI: 43.1%–57.4%) for gemcitabine-based chemotherapy versus 49.3% (95%CI: 41.6%–56.5%) for observation. ConclusionWith 419 patients included, this analysis did not show significant improvement in RFS and no trend in improvement in OS. Gemcitabine-based chemotherapy should not be used as an adjuvant treatment for BTC.

IMPROVING LONG TERM SURVIVAL IN PATIENTS WITH COLORECTAL LIVER METASTASES: LET’S TALK MULTIMODALLY.

Background: Surgical resection is the gold standard treatment for patients with liver-isolated metastatic colorectal cancer (CRC). Consistent improvement in relapse-free survival (RFS) is closely related to proper patient selection criteria, to ever increasing efficacy of chemotherapy regimens, and to the development of other regional treatments combined to systemic chemotherapy. The aim of this study is to report our experience about the efficacy of the above treatments in association with surgery, and to investigate possible prognostic factors that impact survival in these patients.

Systemic adjuvant therapy for high-risk cutaneous melanoma.

Cutaneous melanoma continues to increase in incidence and poses a significant mortality risk. Surgical excision of melanoma in its early stages is often curative. However, patients with resected stages IIB-IV are considered at high risk for relapse and death from melanoma where systemic adjuvant therapy is indicated. The long-studied high-dose interferon-α was shown to improve relapse-free survival (RFS) and overall survival (OS) but is no longer in use. Adjuvant therapy with ipilimumab at 10 mg/kg (ipi10) demonstrated significant RFS and OS improvements but at a high cost in terms of toxicity, while adjuvant ipilimumab 3 mg/kg was shown to be equally effective and less toxic. More recently, the adjuvant therapy for resected stages III-IV melanoma in clinical practice has changed in favor of nivolumab, pembrolizumab, and BRAF-MEK inhibitors dabrafenib plus trametinib (for BRAF mutant melanoma) based on significant improvements in RFS as compared to ipi10 (nivolumab and pembrolizumab) and placebo (dabrafenib plus trametinib). For resected stages IIB-IIC melanoma, pembrolizumab achieved regulatory approval in the United States based on significant RFS benefits. In this article, we review completed and ongoing phase III adjuvant therapy trials. We also briefly discuss neoadjuvant therapy for locoregionally advanced melanoma. Finally, we explore recent studies on predictive and prognostic melanoma biomarkers in the adjuvant setting.

Prognostic Value of Measurable Residual Disease Assessed By Multiparameter Flowcytometry in Patients with NPM1-Mutated Acute Myeloid Leukemia

Prognostic Value of Measurable Residual Disease Assessed By Multiparameter Flowcytometry in Patients with NPM1-Mutated Acute Myeloid Leukemia

Clinical Characteristics and Contemporary Outcomes of Acute Myeloid Leukemia Evolving from Chronic Myelomonocytic Leukemia

Clinical Characteristics and Contemporary Outcomes of Acute Myeloid Leukemia Evolving from Chronic Myelomonocytic Leukemia

S1801: A randomized trial of adjuvant versus neoadjuvant pembrolizumab for melanoma.

TPS9585 Background: Although long term outcomes for most patients with early-stage melanoma is excellent following surgery, patients who have high-risk features such as lymph node involvement have poorer outcomes. Adjuvant therapy (AT) is currently considered for patients with stage III melanoma and selected patients with resected stage IV melanoma. Currently, AT for melanoma is anti-PD-1 or targeted therapy in the presence of a BRAF mutation. At this time, we are not able to predict which patients will derive benefit from AT and experience cure. While curative intent is the goal of treatment for primary melanoma, patients with bulky nodal involvement are at high risk of local or distant recurrence despite upfront surgery. Neoadjuvant treatment (NAT) offers the benefit of an early on-treatment pathological sample that can be profiled for biomarkers and correlated with response and survival. Treating with anti-PD1 while tumor remains visible in the body may generate a stronger immune response against in vivo tumor antigens compared to the traditional adjuvant setting where antigen is presented by microscopic residual tumor burden. Pilot studies of NAT with anti-PD-1 therapy have been initiated in melanoma. Multidisciplinary coordination in these cases is paramount. In these studies, an improvement in relapse-free survival and overall survival has been observed; additionally, pathologic response rates to NAT have been estimated in small studies. Methods: S1801 is a randomized phase II study of AT versus NAT with pembrolizumab (PEM, NCT03698019). Patients with measurable, clinically detectable and resectable cutaneous, acral, and mucosal melanomas without brain metastasis are eligible. Patients with Stage IIIB to oligometastatic, resectable Stage IV are randomized 1:1 to AT or NAT. Patients getting AT undergo surgery first followed by 18 doses of PEM 200 mg IV every 3 weeks. Patients getting NAT receive 3 doses of pre-operative PEM followed by surgery and then 15 doses of adjuvant PEM. Radiation may be given on either arm after surgery, at the investigator’s discretion. Primary endpoint is event-free survival measured from the date of randomization to the date of first documented progression that renders the patient unable to receive planned protocol surgery, failure to begin adjuvant therapy within 84 days of surgery, relapse after surgery, or death due to any cause. Secondary endpoints include RECIST and iRECIST response rates, as well as a number of surgical outcomes. Safety monitoring is conducted with disease progression and toxicity thresholds. The key Translational Medicine objective of this trial is to determine the pathologic response rate to NAT after 3 doses of PEM. Surgical pathology grossing instructions to ensure readout for pathologic response are provided in the form of training slides. Enrollment is at 40% of a planned 500 patients. Clinical trial information: NCT03698019.

Final analysis of overall survival (OS) and relapse-free-survival (RFS) in the intergroup S1404 phase III randomized trial comparing either high-dose interferon (HDI) or ipilimumab to pembrolizumab in patients with high-risk resected melanoma.

9501 Background: We assessed whether or not adjuvant pembrolizumab given over 1 year would improve OS and RFS in comparison to high dose ipilimumab (ipi10) or HDI - the two FDA-approved adjuvant treatments for high risk resected melanoma at the time of study design. Methods: Patients age 18 or greater with resected stages IIIA(N2), B, C and IV were eligible. Patients with CNS metastasis were excluded. At entry, patients must have had complete staging and adequate surgery to render them free of melanoma including completion lymph node dissection for those with sentinel node positive disease. Prior therapy with PD-1 blockade, ipilimumab or interferon was not allowed. Two treatment arms were assigned based on stratification by stage, PD-L1 status (positive vs. negative vs. unknown), and intended control arm (HDI vs. Ipi10). Patients enrolled between 10/2015 and 8/2017 were randomized 1:1 to either the control arm [(1) interferon alfa-2b 20 MU/m2 IV days 1-5, weeks 1-4, followed by 10 MU/m2/d SC days 1, 3, and 5, weeks 5-52 (n=190), or (2) ipilimumab 10 mg/kg IV q3w for 4 doses, then q12w for up to 3 years (n=465)], or the experimental arm [pembrolizumab 200 mg IV q3w for 52 weeks (n=648)]. The study had three primary comparisons: 1) RFS among all patients, 2) OS among all patients, 3) OS among patients with PD-L1+ baseline biopsies. Results: 1,426 patients were screened and 1,345 patients were randomized with 11%, 49%, 34%, and 6% AJCC7 stage IIIA(N2), IIIB, IIIC and IV, respectively. This final analysis was performed per-protocol 3.5 years from the date the last patient was randomized, with 512 RFS and 199 OS events. The pembrolizumab group had a statistically significant improvement in RFS compared to the control group (pooled HDI and ipi10) with HR 0.740 (99.618% CI, 0.571 to 0.958). There was no statistically signifcant improvement in OS in the 1,303 eligible randomized overall patient population with HR 0.837 (96.3% CI, 0.622 to 1.297), or among the 1,070 (82%) patients with PD-L1 positive baseline biopsies with HR 0.883 (97.8% CI, 0.604 to 1.291). Gr 3/4/5 event rates were as follows: HDI 69/9/0%, ipi10 43/5/0.5% and pembrolizumab 17/2/0.3%. Conclusions: Pembrolizumab improves RFS but not OS compared to HDI or ipi10 in the adjuvant treatment of patients with high-risk resected melanoma. Pembrolizumab is a better tolerated adjuvant treatment regimen than HDI or Ipi10. Support: NIH/NCI NCTN grants CA180888, CA180819, CA180820, CA180863; and in part by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Editorial Acknowledgement: With special thanks to Elad Sharon, MD, MPH, and Larissa Korde, MD, MPH. National Cancer Institute, Investigational Drug Branch, for their contributions to this trial, as well as Nageatte Ibrahim, MD, and Sama Ahsan, MD Merck. Clinical trial information: NCT02506153.

A phase 3 randomized study of 5-azacitidine maintenance vs observation after transplant in high-risk AML and MDS patients

AbstractThis study investigated the efficacy and safety of azacitidine maintenance in the posttransplant setting based on the encouraging phase 1/2 reports for azacitidine maintenance in patients with acute myeloid leukemia/myelodysplastic syndrome (AML/MDS). Between 2009 and 2017, a total of 187 patients aged 18 to 75 years were entered into a randomized controlled study of posttransplant azacitidine if they were in complete remission. Patients randomized to the treatment arm (n = 93) were scheduled to receive azacitidine, given as 32 mg/m2 per day subcutaneously for 5 days every 28 days for 12 cycles. The control arm (n = 94) had no intervention. Eighty-seven of the 93 patients started azacitidine maintenance. The median number of cycles received was 4; a total of 29 patients relapsed on study, and 23 patients withdrew from the study due to toxicity, patient's preference, or logistical reasons. Median relapse-free survival (RFS) was 2.07 years in the azacitidine group vs 1.28 years in the control group (P = .43). There was also no significant difference for overall survival, with a median of 2.52 years vs 2.56 years in the azacitidine and control groups (P = .85), respectively. Multivariate Cox regression analysis revealed no improvement in RFS or overall survival with the use of azacitidine as maintenance compared with the control group (hazard ratios of 0.73 [95% confidence interval, 0.49-1.1; P = .14] and 0.84 [95% confidence interval, 0.55-1.29; P = .43]). This randomized trial with azacitidine maintenance showed that a prospective trial in the posttransplant setting was feasible and safe but challenging. Although RFS was comparable between the 2 arms, we believe the strategy of maintenance therapy merits further study with a goal to reduce the risk of relapse in patients with AML/MDS. This trial was registered at www.clinicaltrials.gov as #NCT00887068.

Randomised trial of external-beam radiotherapy alone or with high-dose-rate brachytherapy for prostate cancer: Mature 12-year results

Background and purposeA randomised phase-III trial compared external beam radiotherapy (EBRT) alone with EBRT combined with high-dose-rate brachytherapy boost (HDR-BTb) in localised prostate adenocarcinoma. Previous analysis, at median follow up of 85 months, demonstrated improved relapse free survival (RFS) with EBRT + HDR-BTb. This data has now been updated with a median follow up of 131 months. Materials and methodsFrom December 1997 to August 2005, patients were assigned either to EBRT alone delivering 55 Gy in 20 fractions over 4 weeks or EBRT followed by a temporary high-dose-rate implant delivering 2 × 8·5 Gy over 24 h. The primary endpoint was RFS defined by a PSA rise ≥2.0 µg/l above nadir, clinical progression or death. Actuarial survival rates and Hazard Ratios (HRs) were calculated using the Kaplan–Meier method and Cox’s Proportional Hazard Model, respectively. Secondary endpoints were overall survival (OS), urinary and bowel toxicity. ResultsOne hundred and six patients received EBRT alone and 110 EBRT + HDR-BTb. Median time to relapse was 137 months in the HDR-BTb arm compared to 82 months for EBRT alone (p = 0·01). A 27% risk of recurrence with EBRT alone was observed (p = 0·001), resulting in a 21% improvement in RFS at 12 years with EBRT + HDR-BTb. In multivariate analysis treatment arm, risk category and no androgen deprivation therapy were significant covariates for risk of relapse. Differences in overall survival were not significant. ConclusionAt 12 years there remains a significant improvement in RFS after EBRT + HDR-BTb; both treatments were equitoxic for severe late urinary and bowel events and urethral strictures.