SOC Arm Research Articles

Computational pathology–based HER2 quantification to identify novel biomarkers in gastric cancer (GC).

449 Background: Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate (ADC) approved for treatment of HER2-positive GC/gastroesophageal junction adenocarcinoma (GEJA) after chemotherapy (Japan) and for advanced/metastatic GC/GEJA after a trastuzumab-containing regimen (US/Israel/Singapore). Conventional HER2 immunohistochemistry (IHC) scoring identifies potential responders to trastuzumab but may not be suitable for next-generation ADCs capable of bystander killing, such as T-DXd [Modi NEJM 2022]. Use of computational pathology–based tools enables precise and accurate quantification of HER2 expression and spatial analysis, which enables design of better scores to reflect the T-DXd mechanism of action. Methods: Quantitative continuous scoring (QCS) was performed to quantify HER2 expression and distribution per cell in digitized images of HER2-stained (IHC, Ventana 4B5) GC. A QCS-derived signature was identified, called the continuous spatial proximity score (cSPS), which considers spatial location of tumor cells in addition to HER2 expression level and can be used as a surrogate for potential bystander activity. We retrospectively stratified patients in DESTINY-Gastric01 (DG-01; NCT03329690; T-DXd arm: n=123a; standard of care [SOC] arm: n=59a) using cSPS to give a binary QCS biomarker positive (BM+) or negative (BM−) status. QCS cSPS signature was independently validated on the DESTINY-Gastric02 cohort (DG-02; NCT04014075; n=71a). Results: In the DG-01 cohort, enrolled per HER2-positive status by IHC using ASCO/CAP GC scoring guidelines, median progression-free survival (mPFS) was 5.5a mo with T-DXd and 2.8a mo with SOC. QCS-derived cSPS scores showed significant survival benefit for BM+ vs BM− in the DG-01 T-DXd arm ( P<0.0001; HR=0.37 [0.24-0.58]) and longer mPFS for BM+ (8.3 mo) vs BM− (3.9 mo). Within the SOC arm, this signature showed the inverse prognosis ( P=0.034; HR=2.17 [1.06-4.44]; mPFS, 2.8 mo for BM+ vs 4.9 mo for BM−), strongly suggesting the signature is predictive of T-DXd response. This signature was validated in the DG-02 cohort (mPFS, 5.5 mo on enrollment by IHC status, 10.1 mo for BM+ vs 3.7 mo for BM−; HR=0.24 [0.13-0.45]; P<0.0001). Conclusions: We established QCS, a novel scoring method for tissue biomarkers. Our validated data and results support possible future use of this quantitative approach against manual scoring for identification of patients with GC who may benefit from T-DXd therapy. Clinical trial information: NCT03329690 , NCT04014075 . [Table: see text]

Optimizing Peer Distribution of Syphilis Self-Testing Among Men Who Have Sex with Men in China: A Multi-City Pragmatic Randomized Controlled Trial

Syphilis testing uptake is low among men who have sex with men (MSM) around the world. Syphilis self-testing (SST) may complement facility-based testing; the distribution model is yet to be explored. This study aimed to investigate the effectiveness of peer distribution of syphilis self-testing on promoting syphilis testing. We conducted a three-arm, unblinded, parallel individually randomized controlled trial among MSM in three cities in Guangdong, China. Inclusion criteria were: men who were born biologically male, aged 18 or above, have ever had sex with a man, will refer the interventions to peers, and will take the three-month follow-up survey. Enrolled indexes were randomly assigned in a 1:1:1 ratio into standard-of-care arm (SOC arm), standard SST delivery arm (S-SST arm), and a web-based referral link SST delivery arm (RL-SST arm). The primary outcome was the number of returned photograph-verified syphilis testing results per index. A total number of 300 indexes were enrolled, with 100 indexes in each arm. The number of verified syphilis tests per index conducted by alters was 0.05 in the control arm, 0.51 in the S-SST arm, and 0.31 in the RL-SST arm. The cost per alter tested was $760.60 for SOC, $83.78 for S-SST, and $93.10 for RL-SST. Minimal adverse event was reported among both indexes and alters during the study. This study showed that peer distribution of SST could improve syphilis testing uptake among MSM in China compared to facility-based testing. This approach warrants further consideration as part of expanding syphilis self-testing.

Lisocabtagene Maraleucel (liso-cel) Versus Standard of Care (SOC) with Salvage Chemotherapy Followed By Autologous Stem Cell Transplantation (ASCT) As Second-Line (2L) Treatment in Patients with Relapsed or Refractory Large B-Cell Lymphoma (LBCL): Primary Analysis of the Randomized, Phase 3 Transform Study

Background: Liso-cel is an autologous, CD19-directed, CAR T cell product administered at equal target doses of CD8+ and CD4+ CAR+ T cells. Results of a prespecified interim analysis of the TRANSFORM study (NCT03575351) demonstrated superior efficacy of liso-cel compared with the SOC of salvage immunochemotherapy (CT) followed by high-dose chemotherapy and ASCT in responders, as 2L treatment for patients (pts) with LBCL primary refractory to or relapsed within 12 months of first-line (1L) therapy (Kamdar et al. Lancet 2022). At the interim analysis, the primary endpoint of EFS and key secondary endpoints of CR rate and PFS met statistical significance in favor of liso-cel and OS data were immature. Here we report results from the primary analysis with a median follow-up of 17.5 months. Methods: TRANSFORM is a global, randomized, multicenter, phase 3 study comparing efficacy and safety of liso-cel versus SOC (R-DHAP, R-ICE, or R-GDP followed by BEAM + ASCT) in adults (aged ≤ 75 years) with LBCL primary refractory to or relapsed ≤ 12 months after 1L therapy who were eligible for ASCT. Key inclusion criteria were ECOG PS ≤ 1 and adequate organ function. Pts in the liso-cel arm underwent lymphodepletion with fludarabine/cyclophosphamide followed by liso-cel at a target dose of 100 × 106 CAR+ T cells. Bridging therapy with R-DHAP, R-ICE or R-GDP was allowed at investigator discretion. Pts in the SOC arm received 3 cycles of CT. Responding pts (CR or PR) proceeded to high-dose chemotherapy + ASCT. Crossover to receive liso-cel was allowed for pts in the SOC arm not achieving CR or PR after 3 cycles of CT, not in CR after ASCT, or demonstrating PD at any time. The primary endpoint was event-free survival (EFS) based on independent review committee (IRC). Key secondary endpoints included IRC-assessed CR rate, PFS, and OS. The primary endpoint of EFS was met at the interim analysis and is updated here; thus, only the key secondary endpoints were retested at the primary analysis, as prespecified by the statistical analysis plan. The significance threshold to reject the null hypothesis for the key secondary endpoints was ≤ 0.021 (adjusted for the actual number of events available for analysis and the alpha spent at previous interim analyses). Median follow-up for the primary analysis was 17.5 months (range, 0.9‒37.0). Results: A total of 184 pts were randomized, with 92 pts in each arm. Baseline characteristics were as previously reported, 33% of pts were aged ≥ 65 y, 64% had DLBCL (55% not otherwise specified, 8% transformed from indolent lymphomas), 12.5% had double-hit lymphoma, and 73% were refractory (PD, stable disease, PR, or CR with relapse within 3 months) to 1L therapy. Median (95% CI) EFS was not reached (NR; 9.5-NR) for liso-cel versus 2.4 months (2.2-4.9) for SOC (Figure). CR rate and PFS met statistical significance; CR rate was 74% for liso-cel versus 43% for SOC (P < 0.0001) and median PFS (95% CI) was NR (12.6-NR) for liso-cel versus 6.2 months (4.3-8.6) for SOC (HR, 0.400; P < 0.0001) (Table). Of 26 pts with a PR at the interim analysis, the response deepened to CR for 9 pts at the primary analysis (6/18 in the liso-cel arm; 3/8 in the SOC arm). Of 91 pts treated in the SOC arm, 61 (67%) crossed over to receive liso-cel. At the primary analysis, 66 pts had died (28 in the liso-cel arm and 38 in the SOC arm, including 29 after crossover); the most frequent cause of death was disease progression. Median OS favored liso-cel versus SOC, although it did not meet statistical significance (NR versus 29.9 mo, respectively; HR, 0.724; P = 0.0987). Safety results were consistent with those reported in the interim analysis. Conclusions: This primary analysis, with a median follow-up of 17.5 months, confirmed the clinical benefit of liso-cel over SOC. In TRANSFORM, liso-cel resulted in statistically significant and clinically meaningful improvements in EFS, CR rate, and PFS. These data reinforce liso-cel as a 2L treatment in pts with primary refractory or early relapsed LBCL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Phase 2 Randomized Study Comparing Venetoclax and Azacitidine to Conventional Induction Chemotherapy for Newly Diagnosed Fit Adults with Acute Myeloid Leukemia

Background: The standard therapy for acute myeloid leukemia (AML) for younger, functionally fit patients has not substantially changed in the last 40 years. Intensive induction chemotherapy (IC), with various schedules of cytarabine and an anthracycline, remains the mainstay of therapy. Conventional IC results in complete remission rates of 60-75% of younger and 40-60% of older adults. Despite this, rates of long-term survival and cure remain sub-optimal. These regimens are also associated with significant risk and burden of morbidity, including substantial marrow suppression, mucosal toxicity, high rates of infectious and bleeding complications, potential cardiac injury, prolonged hospitalization, and long-term risk of secondary malignancies. Recently, a placebo-controlled randomized phase 3 trial of older AML patients, and those with comorbidities precluding intensive IC, compared azacitidine and venetoclax to azacitidine and revealed a significant overall survival (OS) advantage for the combination, impressive tolerability, with a markedly higher remission rate at 66% and median OS of 14.7 months, and improvements in other outcome parameters. These recent data compare favorably to outcomes expected from conventional IC, particularly considering their evaluation to date in older, frailer patients, in whom outcomes would be expected to be poorer than younger patients. Based on these considerations, the current randomized phase 2 study seeks to test the hypothesis that treatment with venetoclax and azacitidine will lead to an improved event-free survival (EFS) among fit patients with newly diagnosed AML, when compared to IC. We hypothesized that rates of composite remission for azacitidine and venetoclax will be similar to conventional IC, with an improved safety profile, fewer and less prolonged hospitalizations, lower cost of care, improved candidacy for stem cell transplantation (SCT), and fewer post-SCT complications. Study Design and Methods: This is an open-label, multicenter, phase II randomized clinical trial comparing the therapeutic activity of conventional IC (7+3 regimen or liposomal daunorubicin and cytarabine) to the combination of venetoclax and azacitidine among IC-eligible patients, excluding those with protocol-defined favorable risk genetics or FLT3 mutations. The primary outcome is EFS, where an event is defined as progressive disease (>50% increase in marrow blasts, >50% increase in peripheral blasts, new extramedullary disease), change in therapy due to persistent leukemic disease, relapse after remission, transition to hospice, or death. This study randomizes, in 1:1 fashion, to conventional IC (SOC) or venetoclax plus azacitidine (investigational). Patients will be stratified by age (≥ 65 versus < 65 years old). There is a preselection prior to randomization for either 7+3 or liposomal daunorubicin and cytarabine, to apply to those who are subsequently assigned to the SOC arm. With 172 patients, 86 allocated per arm, the study will achieve 85% power to detect a treatment difference at the one-sided 10% type I error rate, assuming the true hazard ratio is 0.635, based on assumptions of 1-year EFS of 55% on the investigational arm (azacitidine-venetoclax) and 39% on SOC (IC). Before study completion, futility analysis will be trigged after accruing 50% of the subjects and observing 40% of required EFS events. Assuming a failure rate of 30% on the SOC arm and 50% on the investigational arm, if 43 or more events are seen in the latter group, the trial will be stopped for futility. O'Brien-Fleming boundaries set on the p-value due to interim analysis are handled with the Lan-DeMets procedure with the interim p-value = 0.693, and the final p-value = 0.1. Assessments of differences in EFS between the arms will be made with the log rank test; modeling will employ the Cox proportional hazards regression. Differences in EFS at 1-year will also be estimated using the Kaplan Meier method, with standard deviations calculated by Greenwood's formula. Secondary endpoints include composite remission rates, OS, toxicity, rate of measurable residual disease, number and duration of hospitalizations, cost and quality of life measures. Accrual is assumed to be 24 months with a minimum follow up of 15 months, yielding an estimated study duration of 39 months. The study is currently enrolling patients and will be open to accrue at seven hospitals across the United States.

A Prospective, Multicenter, Randomized, Double-Arm Trial to Determine the Impact of the Perimeter B-Series Optical Coherence Tomography and Artificial Intelligence System on Positive Margin Rates in Breast Conservation Surgery

Introduction: Optical coherence tomography (OCT) enables high-resolution, real-time tissue-imaging up to 2mm deep. The Perimeter B-Series OCT System combines wide field-OCT (WF-OCT) with artificial intelligence (AI) to help identify areas suspicious for cancer. The objective of this trial is to assess adjunctive use of WF-OCT and standard care (SOC) in identifying unaddressed positive margins (UPMs). Methods: Prospective, multicenter, randomized, double-arm trial in up to 309 adult women undergoing breast conservation surgery (BCS) for biopsy-confirmed Stage 0-III invasive ductal cancer and/or DCIS, including post-neoadjuvant therapy (NCT05113927). After BCS and SOC intraoperative margin assessment participants will be randomized (2:1) to device or SOC arm. Controls may undergo intraoperative pathology or frozen section analysis, per routine. WF-OCT will be done on all device arm specimens, with an opportunity to excise tissue from the cavity post-analysis, up to 6 total shaves and 2 in each orientation. Results: The study hypothesis is that WF-OCT & AI use will reduce the proportion of subjects with UPM. The primary endpoint is occurrence of ≥1 UPM for a subject; the secondary endpoint is the number of UPMs per subject. Safety includes Adverse Events; false-positive shaves/subject; and BREAST-Q Satisfaction with Breasts. Other outcomes are total excised tissue volume, initial and all procedures; and margin-level effectiveness (sensitivity, specificity, NPV and PPV). Conclusion: Primary endpoint was powered assuming a 15% UPM rate, 90% power, 2:1 allocation, and 10% loss of subjects. Both primary and secondary effectiveness endpoints are based on within-subject comparison of the 2 treatments in the device arm (SOC+WF-OCT).

Lack of Efficacy and Safety of Eculizumab for Treatment of Antibody-Mediated Rejection Following Renal Transplantation

We evaluated the efficacy and safety of eculizumab in comparison with plasmapheresis and intravenous immunoglobulin therapy in renal transplant recipients diagnosed with antibody-mediated rejection (AMR). This was a multicenter, open-label, prospective, randomized analysis. The patients were randomized by therapy type (eg, eculizumab infusions or standard of care [SOC]: plasmapheresis/intravenous immunoglobulin). The patients (ie, eculizumab arm: 7 patients, SOC arm: 4 patients) were evaluated for the continued presence of donor-specific antibodies (DSAs) and C4d (staining on biopsy), as well as histologic evidence, using repeat renal biopsy after treatment. The allograft biopsies revealed that eculizumab did not prevent the progression to transplant glomerulopathy. Only 2 patients in the SOC arm experienced rejection reversal, and no graft losses occurred in either group. After AMR treatment, the DSA titers generally decreased compared to titers taken at the time of AMR diagnosis. There were no serious adverse effects in the eculizumab arm. Eculizumab alone cannot treat AMR effectively and does not prevent acute AMR from progressing to chronic AMR or transplant glomerulopathy. However, it should be considered as a potential alternative therapy because it may be associated with decreased DSA levels.

The Cost-Effectiveness of Axicabtagene Ciloleucel as Second-Line Therapy in Patients with Large B-Cell Lymphoma in the United States: An Economic Evaluation of the ZUMA-7 Trial

Axicabtagene ciloleucel (axi-cel) was found to have superior clinical outcomes compared to standard of care (SOC; salvage chemoimmunotherapy, followed by high-dose therapy with autologous stem cell rescue for responders) for second-line large B-cell lymphoma (2L LBCL) in the pivotal ZUMA-7 trial. The aim of this analysis was to evaluate the cost effectiveness of using axi-cel compared to the current standard 2L LBCL therapy. A 3-state partitioned-survival model estimated the cost effectiveness and budget impact from a payer perspective in the United States. Clinical outcomes were extrapolated based on the pivotal trial. The model calculated expected quality-adjusted life years (QALYs), total costs (in United States dollars [USD], and the incremental cost-effectiveness ratio (ICER), along with the budget impact. Sensitivity and scenario analyses were performed. The proportion alive at 10 years was estimated as 48% for axi-cel and 38% for SOC; median overall survival was estimated at 59 and 24 months for axi-cel and SOC, respectively. Over a lifetime horizon, the model estimated a total of 5.56 and 7.08 QALYs for SOC and axi-cel, respectively, of which 41% and 74% were in the event-free state, respectively. Incremental QALYs and costs were 1.51 and $100,366 USD, resulting in an ICER of $66,381 USD per QALY for axi-cel versus SOC. Despite crossover to subsequent CAR T in the SOC arm, second-line CAR T use was found to improve the quality and length of life compared to SOC. Cost offsets due to subsequent CAR T use led to a limited incremental cost difference. Treatment with axi-cel is a cost-effective option that addresses an important unmet clinical need for patients with LBCL who relapse or are refractory to front-line therapy.

68Ga]Ga-PSMA-11 PET baseline imaging as a prognostic tool for clinical outcomes to [177Lu]Lu-PSMA-617 in patients with mCRPC: A VISION substudy.

5002 Background: In the phase 3 VISION study, gallium (68Ga) gozetotide (68Ga-PSMA-11) PET/CT imaging was used to determine eligibility for lutetium (177Lu) vipivotide tetraxetan (177Lu-PSMA-617). Given that 177Lu-PSMA-617 targets PSMA, we assessed the association between quantitative PSMA imaging parameters and treatment outcomes. Methods: In VISION, adults with mCRPC with ≥ 1 PSMA-positive (+) and no PSMA-negative lesions meeting the exclusion criteria were enrolled. In this sub-study, the association between imaging data from pre-enrollment 68Ga-PSMA-11 PET/CT scans of pts in the 177Lu-PSMA-617 group and clinical outcomes was assessed. Imaging data meeting quality requirements were analyzed for 548/551 pts. PSMA expression was quantified by 5 PET parameters: PSMA+ lesions by region, mean standardized uptake value (SUVmean), maximum SUV (SUVmax), PSMA+ tumor volume, and tumor load (PSMA+ tumor volume × SUVmean). Parameters were extracted from the whole body and 4 regions. Association between PET parameters and radiographic progression-free survival (rPFS; primary objective), overall survival (OS), objective response rate (ORR), and prostate–specific antigen 50 (PSA50) response was assessed. Results: Most pts (92.7%) had PSMA uptake in bone. In both the whole-body and regional analyses, statistically significant associations of PSMA PET parameters to clinical outcomes were observed (whole-body data shown in Table). Higher whole-body SUVmean was associated with improved clinical outcomes; pts in the highest quartile (SUVmean: rPFS, ≥ 10.2; OS, ≥ 9.9) had a median rPFS and OS of 14.1 and 21.4 months, vs 5.8 and 14.5 months for those in the lowest quartile (&lt; 6.0; &lt; 5.7), respectively. Absence of PSMA+ lesions in bone, liver, and lymph node, and lower PSMA+ tumor load, were indicators of good prognosis. Conclusions: Higher SUVmean is strongly associated with improved outcomes with 177Lu-PSMA-617; clinical efficacy for different SUV levels vs the SoC arm is being assessed. Data support use of 68Ga-PSMA-11 PET/CT scan to identify pts who will benefit from PSMA-targeted radioligand therapy.[Table: see text]

NRG-BR002: A phase IIR/III trial of standard of care systemic therapy with or without stereotactic body radiotherapy (SBRT) and/or surgical resection (SR) for newly oligometastatic breast cancer (NCT02364557).

1007 Background: Prospective and retrospective studies of patients (pts) with oligometastatic (OM) disease have supported that metastases (mets) directed treatment (MDT) with SBRT or SR in addition to standard of care systemic therapy (SOC ST) can improve progression-free (PFS) and overall survival (OS) compared with SOC ST alone. However, randomized evidence in oligometastatic breast cancer (OMBC) are lacking. NRG-BR002, a randomized Phase IIR/III trial, sought to determine the efficacy of SOC ST + MDT (SBRT or SR) as first line treatment of OMBC. Methods: OMBC pts with ≤ 4 extracranial mets on standard imaging with controlled primary disease were eligible if on first line SOC ST for ≤ 12 months without progression. Pts were randomized (1:1) to ARM 1 – SOC ST (mainly chemotherapy, endocrine therapy, anti-HER2) or ARM 2 – SOC ST with MDT of all mets. Stratification included mets number (1 vs &gt; 1), ER/PR and Her2 status, and chemotherapy use. Phase IIR targeted sample size was 128 total/116 eligible pts, for 92% power and 1-sided significance level = 0.15 to determine if adding MDT shows a signal for improved PFS (hazard ratio [HR] = 0.55, corresponding to median PFS (mPFS) from 10.5 to 19 months), in order to continue to the full phase III trial for OS. PFS and OS were estimated by Kaplan-Meier and arms compared with log-rank. Results: 125 of the 129 pts randomized were eligible (ARM 1 = 65, ARM 2 = 60). Key characteristics included median age 54, 79% ER+ or PR+/HER2-, 13% HER2+, 8% triple negative. 60% had 1 metastasis and 20% presented synchronously with primary disease. Following randomization, systemic therapy was delivered to 95% in ARM 1 and 93% in ARM 2; ablation: SBRT 93%, SR 2%, and 5% none. The median follow-up was 30 mo. The mPFS (70% CI) in ARM 1 was 23 mo (18, 29) and 19.5 mo (17, 36) in ARM 2; 24 and 36-mo PFS (70% CI) for ARM 1 were 45.7% (38.9, 52.5) and 32.8% (26.0, 39.5) compared with 46.8 (39.2, 54.3) and 38.1 (29.7, 46.6) in ARM 2; HR (70% CI): 0.92 (0.71, 1.17); and 1-sided log-rank p = 0.36. As PFS did not show signal, OS reporting is included: median OS was not reached in either arm; 36-mo OS (95% CI) in ARM 1 71.8% (58.9, 84.7) and ARM 2 68.9% (55.1, 82.6; 2-sided log-rank p = 0.54). Analysis of first failure showed new mets outside index area (Arm 1) /RT field (Arm 2) developed similarly in both arms at 40%. There were fewer new mets inside treated/index area for Arm 2 6.7% vs ARM 1 29.2%, respectively. There were no grade 5 treatment-related adverse events (AEs), 1 grade 4 AE in ARM 1, and 9.7% and 5.3% grade 3 AEs in ARMS 1 and 2, respectively. Circulating tumor cell counts (0 vs ≥1) at baseline were similar in both arms and were not prognostic HR (95% CI): 1.04 (0.54, 2.02). Conclusions: The addition of MDT to SOC ST did not show signal for improved PFS, nor OS difference in patients with OMBC. The trial will not proceed to the Phase III component. Clinical trial information: NCT02364557.

Household Contact Tracing With Intensified Tuberculosis and Human Immunodeficiency Virus Screening in South Africa: A Cluster-Randomized Trial.

BackgroundHousehold contact tracing for tuberculosis (TB) may facilitate diagnosis and access to TB preventive treatment (TPT). We investigated whether household contact tracing and intensive TB/human immunodeficiency virus (HIV) screening would improve TB-free survival.MethodsHousehold contacts of index TB patients in 2 South African provinces were randomized to home tracing and intensive HIV/TB screening or standard of care (SOC; clinic referral letters). The primary outcome was incident TB or death at 15 months. Secondary outcomes included tuberculin skin test (TST) positivity in children ≤14 years and undiagnosed HIV.ResultsFrom December 2016 through March 2019, 1032 index patients (4459 contacts) and 1030 (4129 contacts) were randomized to the intervention and SOC arms. Of intervention arm contacts, 3.2% (69 of 2166) had prevalent microbiologically confirmed TB. At 15 months, the cumulative incidence of TB or death did not differ between the intensive screening (93 of 3230, 2.9%) and SOC (80 of 2600, 3.1%) arms (hazard ratio, 0.90; 95% confidence interval [CI], .66–1.24). TST positivity was higher in the intensive screening arm (38 of 845, 4.5%) compared with the SOC arm (15 of 800, 1.9%; odds ratio, 2.25; 95% CI, 1.07–4.72). Undiagnosed HIV was similar between arms (41 of 3185, 1.3% vs 32 of 2543, 1.3%; odds ratio, 1.02; 95% CI, .64–1.64).ConclusionsHousehold contact tracing with intensive screening and referral did not reduce incident TB or death. Providing referral letters to household contacts of index patients is an alternative strategy to home visits.Clinical Trials RegistrationISRCTN16006202.

CTIM-28. MDNA55, AN INTERLEUKIN-4 RECEPTOR TARGETED IMMUNOTHERAPY, FOR RECURRENT GBM DELIVERED BY CONVECTION ENHANCED DELIVERY (CED)

Abstract BACKGROUND MDNA55 is an IL4R-targeted toxin in development for treatment of recurrent glioblastoma (rGBM). MDNA55 binds to IL4R expressed by tumor cells and non-malignant cells of the tumor microenvironment. METHOD MDNA55-05 was an open-label, single-arm study of MDNA55 delivered by CED as a single treatment in patients with 1st or 2nd recurrence following de novo GBM, IDH wild type status and not indicated for resection at relapse. Dose volumes (up to 60mL) and concentration of MDNA55 (1.5 to 9.0 μg/mL) were studied. RESULTS MDNA55 showed an acceptable safety profile at all doses tested. Median OS (mOS) amongst all subjects was 11.9 months, OS-24 was 20%, and PFS-12 was 27%. Among subjects expressing high levels of IL4R (irrespective of MDNA55 dose) and low levels of IL4R expression administered high dose (≥ 180μg) of MDNA55 (IL4Rhi + IL4Rlo/hd), mOS further improved to 14.0 months with OS-24 of 20%. Unmethylated MGMT promoter status did not affect MDNA55 treatment outcomes. In the IL4Rhi + IL4Rlo/hd population (N=17), mOS was 14.9 months with OS-24 of 22%. Following treatment with high concentrations of MDNA55 (6.0 or 9.0 μg/mL), transient (median of 3 cycles) low dose Avastin (5mg/kg q2w or 7.5mg/kg q3w) was used for symptom control and steroid sparring. Among these subjects, mOS amongst all comers (N=9) and the IL4Rhi + IL4Rlo/hd group (N=8) increased to 21.8 and 18.6 months with OS-24 of 44% and 38%, respectively. CONCLUSIONS MDNA55 shows potential to benefit all rGBM patients treated at high dose irrespective of IL4R expression. In the 1:1 randomized Phase 3 trial, the study will enrol two-thirds of subjects in the SOC arm from a matched external control arm. Unlike conventional RCTs, the hybrid design sets a new precedent for GBM trials, allowing robust OS analysis while significantly reducing the number of subjects randomized to SOC arm.

Point-of-care viral load testing among adolescents and young adults living with HIV in Haiti: a randomized control trial

ABSTRACT HIV viral load (VL) monitoring can reinforce antiretroviral therapy (ART) adherence. Standard VL testing requires high laboratory capacity and coordination between clinic and laboratory which can delay results. A randomized trial comparing point-of-care (POC) VL testing to standard VL testing among 150 adolescents and young adults, ages 10-24 years, living with HIV in Haiti determined if POC VL testing could return faster results and improve ART adherence and viral suppression. Participants received a POC VL test with same-day result (POC arm) or a standard VL test with result given 1 month later (SOC arm). POC arm participants were more likely to receive a test result within 6 weeks than SOC arm participants (94.7% vs. 80.1%; p1000 copies/ml and low self-reported ART adherence was stronger in the POC arm (OR: 6.57; 95%CI: 2.12-25.21) than the SOC arm (OR: 2.62; 95%CI: 0.97-7.44) suggesting more accurate self-report in the POC arm. POC VL testing was effectively implemented in this low-resource setting with faster results and is a pragmatic intervention that may enable clinicians to identify those with high VL to provide enhanced counseling or regimen changes sooner. Trial registration: ClinicalTrials.gov identifier: NCT03288246.

Cost-Effectiveness Analysis of Remdesivir Treatment in COVID-19 Patients Requiring Low-Flow Oxygen Therapy: Payer Perspective in Turkey

IntroductionThis study aims to evaluate the cost-effectiveness of remdesivir compared to other existing therapies (SoC) in Turkey to treat COVID-19 patients hospitalized with < 94% saturation and low-flow oxygen therapy (LFOT) requirement.MethodsWe compared remdesivir as the treatment for COVID-19 with the treatments in the Turkish treatment guidelines. Analyses were performed using data from 78 hospitalized COVID-19 patients with SpO2 < 94% who received LFOT in a tertiary healthcare facility. COVID-19 episode costs were calculated for 78 patients considering the cost of modeled remdesivir treatment in the same group from the payer’s perspective. The incremental cost-effectiveness ratio (ICER) per quality-adjusted life-year (QALY) was calculated for remdesivir versus the SoC for the population identified. For Turkey, a reimbursement threshold value between USD 8599 (1 × per capita gross domestic product—GDP) and USD 25.797 (3 × GDP) per QALY was used.ResultsIn the remdesivir arm, the length of hospital stay (LOS) was 3 days shorter than the SOC. The low ventilator requirement in the remdesivir arm was one factor that decreased the QALY disutility value. In patients who were transferred to intensive care unit (ICU) from the ward, the mean LOS was 17.3 days (SD 13.6), and the mean cost of stay was USD 155.3/day (SD 168.0), while in patients who were admitted to ICU at baseline, the mean LOS was 13.1 days (SD 13.7), and the mean cost of stay was USD 207.9/day (SD 133.6). The mean cost of episode per patient was USD 3461.1 (SD 2259.8) in the remdesivir arm and USD 3538.9 (SD 3296.0) in the SOC arm. Incremental QALYs were estimated at 0.174. Remdesivir treatment was determined to be cost saving vs. SoC.ConclusionsRemdesivir, which results in shorter LOS and lower rates of intubation requirements in ICU patients than existing therapies, is associated with higher QALYs and lower costs, dominating SoC in patients with SpO2 < 94% who require oxygen support.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12325-021-01874-9.

Is There a Place for Induction Therapy With Polyclonal Antibodies to Improve Renal Function After Liver Transplantation?

Is There a Place for Induction Therapy With Polyclonal Antibodies to Improve Renal Function After Liver Transplantation?

72. Remdesivir vs Standard Care in Patients with Moderate covid-19

BackgroundRemdesivir (RDV) shortens time to recovery time in patients with severe COVID-19. Its effect in patients with moderate COVID-19 remains unclear.MethodsWe conducted an open-label, phase 3 trial (NCT04252664) involving hospitalized patients with confirmed SARS-CoV-2 infection, evidence of pulmonary infiltrates, and oxygen saturation >94% on room air. Patients were randomly assigned 1:1:1 to receive up to 5d or 10d of RDV with standard of care (SoC), or SoC alone; patients could be discharged prior to completing per-protocol assigned treatment duration. RDV was dosed intravenously at 200 mg on d1, 100 mg daily thereafter. Patients were evaluated daily while hospitalized, and via telephone if discharged. The primary endpoint was clinical status on d11 assessed on a 7-point ordinal scale. Results regarding the primary endpoint are expected to be published before IDWeek 2020; we plan to present d28 results at the meeting.ResultsIn total, 584 patients underwent randomization and started their assigned treatment (191, 5d RDV; 193, 10d RDV; 200, SoC). By d11, ³ 2 point improvement on the ordinal scale occurred in 70% of patients in the 5d arm, 65% in the 10d arm, and 61% in the SoC arm. Patients in the 5d RDV arm were significantly more likely to have an improvement in clinical status than those receiving SoC (odds ratio [OR], 1.65; 95% confidence interval [CI], 1.09–2.48; P=0.017); OR of improvement for the 10d RDV arm compared to SoC was 1.31 (95% CI, 0.88–1.95]; p=0.183). This improvement in the 5-day arm over the SOC arm was noted from d6 through d11. We observed a peak of discharges corresponding with the assigned treatment duration of RDV, with increased discharges at d6 in the 5-day arm and at d11 in the 10-day arm. A worsening of clinical status of ≥ 1 point in the ordinal scale was observed more commonly in the SoC am (n=19, 10%) versus the 5d RDV (n=7, 4%) and 10d RDV (n=9, 5%).ConclusionRDV for up to 5 days was superior to SoC in improving the clinical status of patients with moderate COVID-19 by d11. We will report d28 outcomes at the meeting.Disclosures Francisco M. Marty, MD, Allovir (Consultant)Amplyx (Consultant)Ansun (Scientific Research Study Investigator)Avir (Consultant)Cidara (Scientific Research Study Investigator)F2G (Consultant, Scientific Research Study Investigator)Kyorin (Consultant)Merck (Consultant, Grant/Research Support, Scientific Research Study Investigator)New England Journal of Medicine (Other Financial or Material Support, Honorarium for Video)Regeneron (Consultant, Scientific Research Study Investigator)ReViral (Consultant)Scynexis (Scientific Research Study Investigator)Symbio (Consultant)Takeda (Scientific Research Study Investigator)United Medical (Consultant)WHISCON (Scientific Research Study Investigator) Prashant Malhotra, MD, Gilead Sciences Inc. (Scientific Research Study Investigator) Robert L. Gottlieb, MD, Gilead Sciences Inc. (Scientific Research Study Investigator) Karen T. Tashima, MD, Bristol-Myers Squibb (Research Grant or Support)Gilead Sciences Inc. (Grant/Research Support, Scientific Research Study Investigator)GlaxoSmithKline (Research Grant or Support)Merck (Research Grant or Support)Tibotec (Research Grant or Support)Viiv Healthcare (Research Grant or Support) Massimo Galli, MD, Gilead Sciences Inc. (Grant/Research Support, Scientific Research Study Investigator, Advisor or Review Panel member, Other Financial or Material Support, Personal fees) Louis Yi Ann Chai, MD, Gilead Sciences Inc. (Scientific Research Study Investigator) Devi SenGupta, MD, Gilead Sciences Inc. (Employee, Shareholder) Robert H. Hyland, MD, Gilead Sciences Inc. (Employee, Shareholder) Hongyuan Wang, PhD, Gilead Sciences Inc. (Employee, Shareholder) Lijie Zhong, PhD, Gilead Sciences Inc. (Employee, Shareholder) Huyen Cao, MD, Gilead Sciences Inc. (Employee, Shareholder) Anand Chokkalingam, PhD, Gilead Sciences (Employee) Anu Osinusi, MD, Gilead Sciences (Employee) Diana M. Brainard, MD, Gilead Sciences (Employee) Michael Brown, MD, Gilead Sciences Inc. (Scientific Research Study Investigator) Ane Josune Goikoetxea, MD, Gilead Sciences Inc. (Scientific Research Study Investigator) Mamta Jain, MD, Gilead Sciences Inc. (Scientific Research Study Investigator, Research Grant or Support)GlaxoSmithKline (Advisor or Review Panel member)Janssen (Research Grant or Support)Merck (Research Grant or Support) David Shu Cheong Hui, MD, Gilead Sciences Inc. (Scientific Research Study Investigator) Enos Bernasconi, MD, Gilead Sciences Inc. (Scientific Research Study Investigator) Christoph Spinner, MD, AbbVie (Advisor or Review Panel member, Other Financial or Material Support, Travel)Bristol-Myers Squibb (Grant/Research Support, Advisor or Review Panel member, Other Financial or Material Support, Travel)Gilead Sciences Inc. (Grant/Research Support, Scientific Research Study Investigator, Advisor or Review Panel member, Other Financial or Material Support, Travel)Janssen (Grant/Research Support, Advisor or Review Panel member, Other Financial or Material Support, Travel)MSD (Grant/Research Support, Advisor or Review Panel member, Other Financial or Material Support, Travel)Viiv Healthcare (Grant/Research Support, Advisor or Review Panel member, Other Financial or Material Support, Travel)

Using artificial intelligence tools in answering important clinical questions: The KEYNOTE-183 multiple myeloma experience

The phase III, randomized, active-controlled, multicenter, open-label KEYNOTE-183 study (NCT02576977) evaluating pomalidomide and low dose dexamethasone (standard-of-care [SOC]) with or without pembrolizumab in patients with refractory or relapsed and refractory multiple myeloma (rrMM) was placed on full clinical hold by the US FDA on July 03, 2017 due to an imbalance in the number of deaths between arms. Clinically-led subgroup analyses are typically used to shed light on clinical findings. However, this approach is not always successful. We propose a systematic approach using the artificial intelligence tools to identifying risk factors and subgroups contributing to the overall death (prognostic) or to the excess death observed in the pembrolizumab plus SOC arm (predictive) of the KEYNOTE-183 study. In KEYNOTE-183, with a data cutoff date of June 02, 2017, we identified plasmacytoma as a prognostic factor, and ECOG performance status as a predictive factor of death. In addition, a qualitative interaction was observed between ECOG performance status and the treatment arm. The subsequent subgroup analysis based on ECOG performance status confirmed that more deaths were associated with pembrolizumab plus SOC versus SOC alone in patients with ECOG performance status 1.

Complete response to immune checkpoint inhibitors-based therapy in advanced renal cell carcinoma patients. A meta-analysis of randomized clinical trials

BackgroundA major breakthrough with immunotherapy is its potential to achieve complete responses (CR) in a subset of advanced renal cell carcinoma (RCC) patients. We aim at evaluating the incidence and relative risk (RR) of CR in RCC patients treated with immune checkpoint inhibitors (ICIs). Materials and methodsSearching the MEDLINE/PubMed, Cochrane Library and ASCO Meeting abstracts prospective studies were identified. The proportion of patients with CR events and the derived 95% confidence intervals (CIs) were calculated for each study. Combined relative risks (RRs) and 95% CIs were calculated using fixed- or random-effects methods. The analysis was performed in the intention to treat population, in the PD-L1 expressing (≥1%) RCC tumors and in patients treated with the combination of ICIs and anti-VEGFR tyrosine kinase inhibitors. ResultsSix articles were considered for final analysis (total of 4.531 patients). The incidence of CR was 6.2% with ICIs and 2.6% with SOC. Treatment with ICIs significantly increased the risk of achieving CR compared to SOC (RR = 2.40; P = 0.001). This data was confirmed for patients treated with the combination of ICIs plus anti-VEGFR tyrosine kinase inhibitors (RR = 2.50; P = 0.002). In PD-L1 positive tumors, the incidence of CR was 10.0% with ICIs and 4.0% in the SOC arm (RR = 2.49; P < 0.0001). ConclusionsICIs provide higher rates of CR compared to SOC, even higher in patients with PD-L1 positive tumors.

P1755EFFICACY AND SAFETY ECULIZUMAB FOR THE TREATMENT OF ANTIBODY MEDIATED REJECTION FOLLOWING RENAL TRANSPLANTATION

Abstract Background and Aims : We evaluated the efficacy and safety of eculizumab in comparison with plasmapheresis (PP) and intravenous immunoglobulin (IVIG) therapy in renal transplant recipients diagnosed with antibody-mediated rejection (AMR). Methods This was a multi-center, open-label, prospective, randomized analysis. The patients were randomized as to therapy type (eculizumab infusions or standard of care, SOC: PP/IVIG). The patients (eculizumab arm: 7 patients, SOC arm: 4 patient) were evaluated for the continuing presence of donor-specific antibodies (DSAs) and C4d (staining on biopsy), as well as histological evidence, using repeat renal biopsies after treatment. Results The allograft biopsies revealed that eculizumab did not prevent the progression to transplant glomerulopathy. Only 2 patients in the SOC arm experienced rejection reversal, and no graft losses occurred in either group. Following AMR treatment, the DSA titers generally decreased compared to titers taken at the time of AMR diagnosis. There were no serious adverse effects in the eculizumab arm. Conclusion Eculizumab alone is not sufficient to treat AMR and does not prevent acute AMR from progressing to chronic AMR or to transplant glomerulopathy. However, it should be considered as a potential alternative therapy because it may be associated with decreased DSA levels.

Meropenem vs standard of care for treatment of neonatal late onset sepsis (NeoMero1): A randomised controlled trial.

BackgroundThe early use of broad-spectrum antibiotics remains the cornerstone for the treatment of neonatal late onset sepsis (LOS). However, which antibiotics should be used is still debatable, as relevant studies were conducted more than 20 years ago, recruited in single centres or countries, evaluated antibiotics not in clinical use anymore and had variable inclusion/exclusion criteria and outcome measures. Moreover, antibiotic-resistant bacteria have become a major problem in many countries worldwide. We hypothesized that efficacy of meropenem as a broad-spectrum antibiotic is superior to standard of care regimens (SOC) in empiric treatment of LOS and aimed to compare meropenem to SOC in infants aged <90 days with LOS.Methods and findingsNeoMero-1 was a randomized, open-label, phase III superiority trial conducted in 18 neonatal units in 6 countries. Infants with post-menstrual age (PMA) of ≤44 weeks with positive blood culture and one, or those with negative culture and at least with two predefined clinical and laboratory signs suggestive of LOS, or those with PMA >44 weeks meeting the Goldstein criteria of sepsis, were randomized in a 1:1 ratio to receive meropenem or one of the two SOC regimens (ampicillin+gentamicin or cefotaxime+gentamicin) chosen by each site prior to the start of the study for 8–14 days. The primary outcome was treatment success (survival, no modification of allocated therapy, resolution/improvement of clinical and laboratory markers, no need of additional antibiotics and presumed/confirmed eradication of pathogens) at test-of-cure visit (TOC) in full analysis set. Stool samples were tested at baseline and Day 28 for meropenem-resistant Gram-negative organisms (CRGNO). The primary analysis was performed in all randomised patients and in patients with culture confirmed LOS. Proportions of participants with successful outcome were compared by using a logistic regression model adjusted for the stratification factors. From September 3, 2012 to November 30th 2014, total of 136 patients (instead of planned 275) in each arm were randomized; 140 (52%) were culture positive. Successful outcome at TOC was achieved in 44/136 (32%) in the meropenem arm vs. 31/135 (23%) in the SOC arm (p = 0.087). The respective numbers in patients with positive cultures were 17/63 (27%) vs. 10/77 (13%) (p = 0.022). The main reason of failure was modification of allocated therapy. Treatment emergent adverse events occurred in 72% and serious adverse events in 17% of patients, the Day 28 mortality was 6%. Cumulative acquisition of CRGNO by Day 28 occurred in 4% of patients in the meropenem and 12% in the SOC arm (p = 0.052).ConclusionsWithin this study population, we found no evidence that meropenem was superior to SOC in terms of success at TOC, short term hearing disturbances, safety or mortality were similar in both treatment arms but the study was underpowered to detect the planned effect. Meropenem treatment did not select for colonization with CRGNOs. We suggest that meropenem as broad-spectrum antibiotic should be reserved for neonates who are more likely to have Gram-negative LOS, especially in NICUs where microorganisms producing extended spectrum- and AmpC type beta-lactamases are circulating.

First Analysis of the UKALL14 Phase 3 Randomised Trial to Determine If the Addition of Rituximab to Standard Induction Chemotherapy Improves EFS in Adults with Precursor B-ALL (CRUK/09/006)

First Analysis of the UKALL14 Phase 3 Randomised Trial to Determine If the Addition of Rituximab to Standard Induction Chemotherapy Improves EFS in Adults with Precursor B-ALL (CRUK/09/006)