Citations

Abstract Approximately one‐third of patients diagnosed with Hodgkin lymphoma presenting with Stage IV disease do not survive past 5 years. We present updated efficacy and safety analyses in high‐risk patient subgroups, defined by Stage IV disease or International Prognostic Score (IPS) of 4–7, enrolled in the ECHELON‐1 study that compared brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (A + AVD) versus doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as first‐line therapy after a median follow‐up of 37.1 months. Among patients treated with A + AVD ( n = 664) or ABVD ( n = 670), 64% had Stage IV disease and 26% had an IPS of 4–7. Patients with Stage IV disease treated with A + AVD showed consistent improvements in PFS at 3 years as assessed by investigator (hazard ratio [HR], 0.723; 95% confidence interval [CI], 0.537–0.973; p = 0.032). Similar improvements were seen in the subgroup of patients with IPS of 4–7 (HR, 0.588; 95% CI, 0.386–0.894; p = 0.012). The most common adverse events (AEs) in A + AVD‐treated versus ABVD‐treated patients with Stage IV disease were peripheral neuropathy (67% vs. 40%) and neutropenia (71% vs. 55%); in patients with IPS of 4–7, the most common AEs were peripheral neuropathy (69% vs. 45%), neutropenia (66% vs. 55%), and febrile neutropenia (23% vs. 9%), respectively. Patients in high‐risk subgroups did not experience greater AE incidence or severity than patients in the total population. This updated analysis of ECHELON‐1 shows a favorable benefit‐risk balance in high‐risk patients.

AbstractBackgroundMagnetic Resonance Spectroscopy (MRS) is a non‐invasive technique assessing the concentration of various metabolites within the brain, both cross‐sectionally to characterize disease type and severity, and longitudinally to assess disease progression and potential treatment efficacy in the context of disease‐modifying interventions. In such context, the involvement of multiple imaging facilities inevitably introduces variability, whose amount must be known to inform on comparability between sites and sensitivity to change. Our objective is to study variability in the concentration of various brain metabolites using a dedicated MRS phantom and assess impact of field strength.Methods30 sites are being considered to participate in an on‐going clinical trial in metachromatic leukodystrophy. Site qualification mandates the scanning of a dedicated MRS phantom. 30 of these HD‐polyethylene spheres were simultaneously manufactured and filled with the same mixture of chemicals mimicking main metabolite concentrations. To date, 14 sites provided data (5 1.5T scanners and 9 3T). All sites implemented a standardized single‐voxel MRS sequence. MRS voxel was placed within the phantom and acquisition repeated 3 times. Spectra were centrally analyzed using LCModel v6.3 and quality controlled by Bioclinica. Repeat acquisitions were requested for parameter deviations, voxel positioning and/or shimming issues. Results only include passing datasets. Coefficient of Variation (CV) was calculated for NAA/Cr, Cho/Cr, mI/Cr, Glx/Cr and Lac/Cr ratios for each site and overall. LCModel quality metrics (FHWM and S/N) were also extracted to assess spectra quality. Comparison between field strengths was carried out using t‐tests.ResultsAverage CV by site was 2.0% for NAA/Cr (2.5% at 1.5T and 1.8% at 3T), 2.4% for Cho/Cr, 3.0% for mI/Cr, 4.5% for Glx/Cr and 6.1% for Lac/Cr. CVs were generally lower at 3T (except for Lac/Cr) although difference was not significant. As expected, Signal‐to‐Noise was higher at 3T (p=0.05). Overall CV by metabolite across scanners was much higher (ranging from 4.6% for Cho/Cr up to 12.1% for Lac/Cr).ConclusionMRS measures of metabolite concentrations have low variability at scanner‐level, insensitive to field strength. Nevertheless, variability across sites is much higher and would require, if possible, cross‐calibration. These phantom data make such calibration possible and will improve sensitivity of subject data analyses.

Abstract BACKGROUND The original 3-arm CODEL design included a radiotherapy (RT)-alone control arm, an RT plus temozolomide (TMZ) arm, and an exploratory TMZ-alone arm. We report the analysis involving patients treated per the initial design. METHODS Adults (18+ years) with newly-diagnosed 1p/19q codeleted WHO grade III oligodendroglioma were randomized to RT (5940 cGy) alone (Arm A); RT with concomitant and adjuvant TMZ (Arm B); or TMZ alone (Arm C). Primary endpoint was OS, Arm A vs. B. Secondary comparisons were performed for OS and PFS, comparing pooled RT arms with the TMZ-alone arm. RESULTS 36 patients were randomized equally to the three arms. At median follow-up of 7.5 years, 83.3% (10/12) TMZ-alone patients had progressed, versus 37.5% (9/24) patients on the RT arms. PFS was shorter in TMZ-alone patients compared to RT-treated patients (HR=3.12; 95% CI: 1.26, 7.69; p=0.014). Death from disease progression occurred in 3/12 (25%) of TMZ-alone patients and 4/24 (16.7%) of RT-treated patients. OS did not statistically differ between arms, although this comparison was underpowered. After adjustment for IDH status (mutated vs. wildtype) in a Cox regression model, with IDH status and RT treatment status as co-variables (Arm C vs pooled A and B), PFS remained shorter for patients not receiving RT (HR= 3.33; 95% CI: 1.31, 8.45; p=0.011), and OS differences remained non-significant ((HR = 2.78; 95% CI 0.58, 13.22, p=0.20). Grade 3+ adverse events occurred in 25%, 42% and 33% patients (Arms A, B and C, respectively). Neurocognitive assessments, comparing baseline and 3 month timepoints, showed no significant differences between arms. CONCLUSIONS TMZ-alone treated patients experienced significantly shorter PFS than patients treated on the pooled RT arms, which remained significant when adjusting for IDH status. CODEL has been redesigned to compare the efficacy and toxicity of RT+PCV versus RT+TMZ. Clinicaltrials.gov Identifier: NCT00887146. Support: U10CA180821, U10CA180882, https://acknowledgments.alliancefound.org.

AbstractBackgroundHepatectomy is standard treatment for colorectal liver metastases; however, it is unclear whether liver metastases from other primary cancers should be resected or not. The Japanese Society of Hepato‐Biliary‐Pancreatic Surgery therefore created clinical practice guidelines for the management of metastatic liver tumors.MethodsEight primary diseases were selected based on the number of hepatectomies performed for each malignancy per year. Clinical questions were structured in the population, intervention, comparison, and outcomes (PICO) format. Systematic reviews were performed, and the strength of recommendations and the level of quality of evidence for each clinical question were discussed and determined. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess evidence and make recommendations.ResultsThe eight primary sites were grouped into five categories based on suggested indications for hepatectomy and consensus of the guidelines committee. Fourteen clinical questions were devised, covering five topics: (1) diagnosis, (2) operative treatment, (3) ablation therapy, (4) the eight primary diseases, and (5) systemic therapies. The grade of recommendation was strong for one clinical question and weak for the other 13 clinical questions. The quality of the evidence was moderate for two questions, low for 10, and very low for two.A flowchart was made to summarize the outcomes of the guidelines for the indications of hepatectomy and systemic therapy.ConclusionsThese guidelines were developed to provide useful information based on evidence in the published literature for the clinical management of liver metastases, and they could be helpful for conducting future clinical trials to provide higher‐quality evidence.

Adrenocortical carcinoma (ACC) is an orphan disease lacking effective systemic treatment options. The low incidence of the disease and high cost of clinical trials are major obstacles in the search for improved treatment strategies. As a novel approach, registry-based clinical trials have been introduced in clinical research, so allowing for significant cost reduction, but without compromising scientific benefit. Herein, we describe how the European Network for the Study of Adrenal Tumours (ENSAT) could transform its current registry into one fit for a clinical trial infrastructure. The rationale to perform randomized registry-based trials in ACC is outlined including an analysis of relevant limitations and challenges. We summarize a survey on this concept among ENSAT members who expressed a strong interest in the concept and rated its scientific potential as high. Legal aspects, including ethical approval of registry-based randomization were identified as potential obstacles. Finally, we describe three potential randomized registry-based clinical trials in an adjuvant setting and for advanced disease with a high potential to be executed within the framework of an advanced ENSAT registry. Thus we, therefore, provide the basis for future registry-based trials for ACC patients. This could ultimately provide proof-of-principle of how to perform more effective randomized trials for an orphan disease.

Background Maintenance therapy improves PFS in NDMM pts. Additional active, well-tolerated treatment options that are suitable for long-term administration are required. The international, multicenter, double-blind, placebo-controlled, phase 3 TOURMALINE-MM4 trial (NCT02312258) of the oral PI ixazomib as maintenance therapy post-induction in non-transplant NDMM pts met its primary endpoint of PFS. Ixazomib demonstrated a significant and clinically meaningful benefit vs placebo, with a manageable and well-tolerated toxicity profile. Feasible, tolerable options for long-term therapy are particularly important in this setting, as pts are often elderly and/or frail. We report herein a subgroup analysis of TOURMALINE-MM4 according to age and frailty status. Methods Pts who achieved ≥partial response (PR) after 6-12 months of standard-of-care induction therapy were randomized 3:2 to ixazomib or placebo maintenance for up to 24 months. The sum of 4 components - age (<75 vs 75-80 vs >80 years; score 0 vs 1 vs 2), the Katz Index of Independence in Activities of Daily Living (ADL; >4 vs ≤4, score 0 vs 1), the Lawton Instrumental ADL Scale (>5 vs ≤5, score 0 vs 1), and the Charlson Comorbidity Index (≤1 vs ≥2, score 0 vs 1) - was used to classify pts as fit (total score: 0), unfit (score: 1), or frail (score: ≥2). Analyses of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 and MY20 modules were conducted to evaluate the effects of treatment on QoL within subgroups defined by frailty status and age. Results In the ixazomib (n=425) vs placebo (n=281) arms, there were similar proportions of pts aged <65, 65-74, and ≥75 years and of pts classified as fit, unfit, and frail (Table 1). Baseline disease and treatment characteristics were generally balanced in ixazomib vs placebo pts across the different age and frailty groups, with some numerical differences observed. In pts aged <65 years, higher rates of International Staging System (ISS) stage III disease and fit pts and a lower rate of complete (CR) or very good partial (VGPR) response post-induction were seen (Table 1). Across frailty groups, a higher rate of CR or VGPR was seen in fit pts, a lower rate of ISS stage III disease was seen in unfit pts, and a higher rate of ISS stage III disease and a lower rate of CR or VGPR were seen in frail pts (Table 1). PFS benefit with ixazomib vs placebo was seen across age groups, with hazard ratios (HRs) of 0.576 (95% confidence interval [CI] 0.299-1.108, p=0.095, median 11.0 vs 9.3 months) in pts aged <65 years, 0.615 (95% CI 0.467-0.810, p<0.001, median 17.9 vs 9.3 months) in pts aged 65-74, and 0.740 (95% CI 0.537-1.019, p=0.064, median 16.7 vs 10.2 months) in pts aged ≥75 years. HRs for time to progression (TTP) were similar to those for PFS. PFS benefit with ixazomib vs placebo was also seen across frailty groups (Figure), with similar HRs for TTP. Rates of grade ≥3 treatment-emergent adverse events (TEAEs), serious TEAEs, and discontinuation due to TEAEs were higher or similar with ixazomib vs placebo across age and frailty subgroups (Table 2). Rates were generally somewhat higher in older age groups and in unfit/frail pts in both arms; nevertheless, rates of discontinuation due to TEAEs across groups were <20%, even in pts aged ≥75 years and frail pts (Table 2). With ixazomib, rates of common gastrointestinal TEAEs were similar across age groups; rash and liver impairment appeared less common and peripheral neuropathy more common in older pts (Table 2). Covariate-adjusted changes in QoL subscales from baseline were estimated at each cycle using repeated measures linear mixed models stratified by frailty status. In all frailty groups, the mean changes in each treatment arm were small over time (<10 points on a 0-100 scale) and similar between arms, indicating that continued treatment with ixazomib vs placebo maintenance did not adversely affect pts' QoL. Analyses by age were generally consistent with the results by frailty. Conclusions Ixazomib as post-induction maintenance therapy in non-transplant NDMM pts results in PFS benefits vs placebo regardless of age or frailty status. Ixazomib appeared generally well tolerated across groups, with TEAE rates in both arms generally elevated in elderly/frail vs younger/fit pts. Ixazomib is a feasible and effective maintenance option for prolonging PFS across this heterogeneous pt population. Disclosures Bringhen: Takeda: Consultancy; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Vorog:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Labotka:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Wang:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Cherepanov:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Cain:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Manne:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Dimopoulos:Celgene: Honoraria; Janssen: Honoraria; Takeda: Honoraria; Bristol-Myers Squibb: Honoraria; Beigene: Honoraria; Amgen: Honoraria. OffLabel Disclosure: Use of the oral proteasome inhibitor ixazomib as maintenance therapy in patients with newly diagnosed multiple myeloma not undergoing stem cell transplantation