Interim Efficacy Research Articles

Neoadjuvant Pembrolizumab in Stage I-III Deficient Mismatch Repair Colon Cancer: A Clinical Trial.

This clinical trial investigated the safety and efficacy of single-cycle pembrolizumab in patients with localized deficient mismatch repair (dMMR) colon cancer. Neoadjuvant immunotherapy has induced remarkable rates of pathological complete response in patients with dMMR colon cancer. However, the optimal length and type of treatment are yet to be determined. This was an investigator-initiated, multicenter, single-arm, phase II study (ClinicalTrials.gov: NCT05662527) investigating the safety and efficacy of neoadjuvant pembrolizumab in patients with stage I-III dMMR colon cancer. Patients received a single cycle of pembrolizumab 4mg/kg (maximum 400mg) and underwent surgery three to five weeks later. An interim safety and efficacy analysis after including 42 patients was pre-planned. The primary outcomes were safety and efficacy (pathological complete response in more than 20% of patients). Between February 2023 and September 2023, 42 patients were enrolled at five Danish hospitals. All patients received pembrolizumab and underwent surgery, except one patient who refused to undergo surgery. Surgery was performed a median of 32 days after pembrolizumab treatment. Twenty surgical complications were observed in 16 of 41 patients (39%), three of which were above Clavien-Dindo grade 2. Two were grade 3b, and one was a surgery-related grade 5 gastric ulcer perforation. Three adverse events were grade 3. No grade 4 or 5 adverse events were reported. Of the evaluable patients, 46% (19/41) achieved a pathological complete response, while 61% had a major pathological response. In conclusion, neoadjuvant single-cycle pembrolizumab was well tolerated and effective in patients with localized dMMR colon cancer. Thus, the inclusion of patients was continued until 85 patients.

Blinatumomab in Standard-Risk B-Cell Acute Lymphoblastic Leukemia in Children.

B-cell acute lymphoblastic leukemia (B-cell ALL) is the most common childhood cancer. Despite a high overall cure rate, relapsed B-cell ALL remains a leading cause of cancer-related death among children. The addition of the bispecific T-cell engager molecule blinatumomab (an anti-CD19 and anti-CD3 single-chain molecule) to therapy for newly diagnosed standard-risk (as defined by the National Cancer Institute) B-cell ALL in children may improve outcomes. We conducted a phase 3 trial involving children with newly diagnosed standard-risk B-cell ALL who had an average or high risk of relapse. Patients were randomly assigned to receive chemotherapy alone or chemotherapy plus two nonsequential 28-day cycles of blinatumomab. The primary end point was disease-free survival. The data and safety monitoring committee reviewed the results from the first interim efficacy analysis, which included 1440 patients who had undergone randomization (722 to chemotherapy alone and 718 to blinatumomab and chemotherapy) and recommended early termination of randomization. At a median follow-up of 2.5 years, the estimated 3-year disease-free survival (±SE) was 96.0±1.2% with blinatumomab and chemotherapy and 87.9±2.1% with chemotherapy alone (difference in restricted mean survival time, 72 days; 95% confidence interval, 36 to 108; P<0.001 by stratified log-rank test). The estimated 3-year disease-free survival among patients with an average relapse risk was 97.5±1.3% with blinatumomab and chemotherapy and 90.2±2.3% with chemotherapy alone; among those with a high relapse risk, the corresponding values were 94.1±2.5% and 84.8±3.8%. Cytokine release syndrome, seizures, and sepsis of grade 3 or higher were rare during blinatumomab cycles, but the overall incidence of nonfatal sepsis and catheter-related infections was significantly higher among patients with an average relapse risk who had been assigned to receive blinatumomab and chemotherapy than among those assigned to receive chemotherapy alone. Adding blinatumomab to combination chemotherapy in patients with newly diagnosed childhood standard-risk B-cell ALL of average or high risk of relapse significantly improved disease-free survival. (Funded by the National Institutes of Health and others; AALL1731 ClinicalTrials.gov number, NCT03914625.).

Early termination and nonpublication of phase III/IV melanoma clinical trials: a cross-sectional study

Introduction Melanoma is a common cancer worldwide. Introduction of new treatments through clinical trials is essential to reduce the global burden from melanoma; however, it is estimated that 22% of oncological clinical trials are terminated early. We conducted the first cross-sectional study to assess melanoma clinical trial termination and nonpublication with an aim to guide scientists conducting such trials. Methods We identified all phase III/IV clinical trials evaluating melanoma therapies in the ClinicalTrials.gov database between 2010 and 2024. For each trial, we extracted data on the trial’s status, melanoma stage, melanoma subtype, included age, funding sources, trial locations, publication status, and reasons for termination. A descriptive and frequency analysis was performed in JASP 0.19 software. Results A total of 108 trials were analyzed; the majority of trials included stage III/IV melanoma (n = 95), and cutaneous melanoma was the most common subtype. Only 15 trials included pediatric patients. Industrial funding accounted for 74% (n = 80) of trials’ financing. Most of the trials were conducted internationally in North America, Europe, Australia, and New Zealand, with a few trials conducted in South Africa (n = 1), South America (n = 1), or China (n = 5). Early termination was observed in 21% (n = 23) of trials, with no association between early termination and melanoma stage, subtype, age, funding source, or trial locations. Notably, the most common reason for early termination was publication of interim efficacy and safety results (n = 14/23). Conclusion Our study confirms that early termination of phase III and IV melanoma trials doesn’t raise a significant concern; however, diversified funding and broader geographic representation are needed to create more equitable and inclusive trials. We also suggest conducting further cross-sectional studies on phase I/II melanoma trials.

Daratumumab Versus Lenalidomide As Maintenance Therapy in Newly Diagnosed Multiple Myeloma - Interim Efficacy Results of a Randomized Clinical Trial

Daratumumab Versus Lenalidomide As Maintenance Therapy in Newly Diagnosed Multiple Myeloma - Interim Efficacy Results of a Randomized Clinical Trial

GenePHIT phase 2 study design: a double blind, placebo-controlled trial to assess efficacy, safety, and tolerability of AB-1002 gene therapy in adults with heart failure

Abstract Introduction Heart failure (HF) is associated with substantial morbidity and mortality, highlighting a critical need for novel therapies. AB-1002, an engineered adeno-associated virus (AAV) vector gene therapy candidate, delivers a constitutively active form of protein phosphatase inhibitor (I-1c) to restore cardiomyocyte intracellular calcium homeostasis. Preliminary results from an ongoing Phase (Ph) 1 trial (NCT04179643) of AB-1002 showed favourable safety and tolerability. Here we describe the design of AB-1002 Ph 2 trial (GenePHIT; NCT05598333) to evaluate efficacy, safety, and tolerability. Methods This phase 2 adaptive, double-blind, placebo-controlled, randomised, multi-centre trial (currently United States; European sites planned) includes a 52-week observation and 4-year follow-up period. Eligible patients are ≥18 years of age with non-ischaemic cardiomyopathy and New York Health Association (NYHA) Class III heart failure symptoms (Figure). Patients will be randomised 1:1:1 (n=30–50/treatment arm), including a single dose of AB-1002 administered via antegrade intracoronary infusion at 1 of 2 different doses, or placebo, all in addition to standard of care. The primary endpoint will evaluate efficacy at 52 weeks based on the composite endpoint by modified win ratio, which includes cardiovascular-related death, change in NYHA classification, and for the responders, improvements in left ventricular ejection fraction (LVEF) (≥5%), peak oxygen uptake (pVO2) ≥1.5 mL/kg/min, and 6-min walk test (6MWT) &amp;gt;30 metres. Key secondary efficacy endpoints include functional status and hospitalisations at 24 and 52 weeks, by assessing changes over time in NYHA classification, LVEF, pVO2, 6MWT, biomarkers (N-terminal pro-hormone b-type natriuretic peptide and troponin), quality of life questionnaires (Minnesota Living with Heart Failure, Kansas City Cardiomyopathy), and physiological assessments. Key safety endpoints will be assessed through 52 weeks and include treatment-emergent adverse events (AEs) and serious AEs (SAEs). Exploratory endpoints will evaluate AAV2i8 antibody titres, T-cell response to AAV2i8 capsid and I-1c, and optional right ventricular biopsy testing. Long-term follow-up will assess treatment-emergent AEs and SAEs, and number of HF hospitalisations. Data safety monitoring board assessment will occur every 3 months. Primary efficacy endpoint will compare both active dose groups combined versus placebo using the joint rank test (1). Key secondary endpoints will be analysed using Analysis of Covariance with baseline as a continuous covariate. Multiple imputations will be used to address missing data. Interim efficacy analysis will be performed using a Bayesian adaptive sample size algorithm. Conclusions GenePHIT is currently recruiting and will evaluate the efficacy, safety, and tolerability of intracoronary infusion of AB-1002, an innovative gene therapy targeting ventricular dysfunction in HF.

Alternative Complement Pathway Inhibition with Iptacopan in IgA Nephropathy.

The alternative complement pathway plays a key role in the pathogenesis of IgA nephropathy. Iptacopan specifically binds to factor B and inhibits the alternative pathway. In this phase 3, double-blind, randomized, placebo-controlled trial, we enrolled adults with biopsy-confirmed IgA nephropathy and proteinuria (defined as a 24-hour urinary protein-to-creatinine ratio of ≥1 [with protein and creatinine both measured in grams]) despite optimized supportive therapy. Patients were randomly assigned, in a 1:1 ratio, to receive oral iptacopan (200 mg) or placebo twice daily for 24 months while continuing to receive supportive therapy. The primary objective of this prespecified interim analysis was to assess the efficacy of iptacopan as compared with that of placebo in reducing proteinuria at month 9; the primary end point was the change from baseline in the 24-hour urinary protein-to-creatinine ratio at month 9. The proportion of patients who had a 24-hour urinary protein-to-creatinine ratio of less than 1 at month 9 without receiving rescue or alternative medication or undergoing kidney-replacement therapy (dialysis or transplantation) was a secondary end point. Safety was also assessed. The effect of iptacopan on kidney function will be assessed at the end of the 2-year double-blind treatment period. The main trial population included 222 patients in the iptacopan group and 221 in the placebo group. The interim efficacy analysis included the first 250 patients who underwent randomization in the main trial population (125 patients in each group) and who remained in the trial until month 9 or discontinued the trial by month 9. Safety was assessed in all the patients in the main trial population. At month 9, the adjusted geometric mean 24-hour urinary protein-to-creatinine ratio was 38.3% (95% confidence interval, 26.0 to 48.6; two-sided P<0.001) lower with iptacopan than with placebo. The reduction in proteinuria was supported by consistent results in secondary end point analyses. There were no unexpected safety findings with iptacopan. The incidence of adverse events that occurred during the treatment period was similar in the two groups; most events were mild to moderate in severity and reversible. No increased risk of infection was observed. Among patients with IgA nephropathy, treatment with iptacopan resulted in a significant and clinically meaningful reduction in proteinuria as compared with placebo. (Funded by Novartis; APPLAUSE-IgAN ClinicalTrials.gov number, NCT04578834.).

Efficacy and safety of lumasiran for infants and young children with primary hyperoxaluria type 1: 30-month analysis of the phase 3 ILLUMINATE-B trial

BackgroundPrimary hyperoxaluria type 1 (PH1) is a genetic disorder resulting in overproduction of hepatic oxalate, potentially leading to recurrent kidney stones, nephrocalcinosis, chronic kidney disease, and kidney failure. Lumasiran, the first RNA interference therapeutic approved for infants and young children, is a liver-directed treatment that reduces hepatic oxalate production. Lumasiran demonstrated sustained efficacy with an acceptable safety profile over 12 months in infants and young children (age &amp;lt;6 years) with PH1 in ILLUMINATE-B (clinicaltrials.gov: NCT03905694), an ongoing, Phase 3, multinational, open-label, single-arm study.MethodsHere, we report interim efficacy and safety findings from ILLUMINATE-B following 30 months of lumasiran treatment. Eligible patients had an estimated glomerular filtration rate (eGFR) &amp;gt;45 ml/min/1.73 m2 if ≥12 months old or normal serum creatinine if &amp;lt;12 months old, and a urinary oxalate to creatinine ratio (UOx:Cr) greater than the upper limit of normal. All 18 patients enrolled in ILLUMINATE-B completed the 6-month primary analysis period, entered an extension period of up to 54 months, and continue to participate in the study.ResultsAt Month 30, mean percent change from baseline in spot UOx:Cr was −76%, and mean percent change in plasma oxalate was −42%. eGFR remained stable through Month 30. In 14 patients (86%) with nephrocalcinosis at baseline, nephrocalcinosis grade improved at Month 24 in 12; no patient worsened. In the 4 patients without baseline nephrocalcinosis, nephrocalcinosis was absent at Month 24. Kidney stone event rates were ≤0.25 per person-year through Month 30. Mild, transient injection site reactions were the most common lumasiran-related adverse events (17% of patients).ConclusionIn infants and young children with PH1, long-term lumasiran treatment resulted in sustained reductions in urinary and plasma oxalate that were sustained for 30 months, with an acceptable safety profile. Kidney function remained stable, low kidney stone event rates were observed through Month 30, and nephrocalcinosis grade improvements were observed through Month 24. Clinical Trial Registrationhttps://clinicaltrials.gov, identifier NCT03905694.

Interim safety and efficacy of gene therapy for RLBP1-associated retinal dystrophy: a phase 1/2 trial

Gene therapy holds promise for treatment of inherited retinal dystrophies, a group of rare genetic disorders characterized by severe loss of vision. Here, we report up to 3-year pre-specified interim safety and efficacy results of an open-label first-in-human dose-escalation phase 1/2 gene therapy clinical trial in 12 patients with retinal dystrophy caused by biallelic mutations in the retinaldehyde-binding protein 1 (RLBP1) gene of the visual cycle. The primary endpoints were systemic and ocular safety and recovery of dark adaptation. Secondary endpoints included microperimetry, visual field sensitivity, dominant eye test and patient-reported outcomes. Subretinal delivery of an adeno-associated viral vector (AAV8-RLBP1) was well tolerated with dose-dependent intraocular inflammation which responded to corticosteroid treatment, and focal atrophy of the retinal pigment epithelium as the dose limiting toxicity. Dark adaptation kinetics, the primary efficacy endpoint, improved significantly in all dose-cohorts. Treatment with AAV8-RLBP1 resulted in the resolution of disease-related retinal deposits, suggestive of successful restoration of the visual cycle. In conclusion, to date, AAV8-RLBP1 has shown preliminary safety and efficacy in patients with RLBP1-associated retinal dystrophy. Trial number: NCT03374657.

Interim efficacy of a multicenter cohort study for China Net Childhood Lymphoma mature B-cell lymphoma 2017 regimen in the treatment of pediatric High-grade-B cell lymphoma

Objective: To analyze the mid-term efficacy of the China Net Childhood Lymphoma mature B-cell lymphoma 2017 (CNCL-B-NHL-2017) regimen in treating children with high-grade B-cell lymphoma (HGBL). Methods: Clinical and pathological data of HGBL children aged≤18 years admitted to 16 hospitals of the Chinese Children's Lymphoma Collaborative Group (CNCL) from May 2017 to April 2021 were collected retrospectively. They were divided in to high-grade B-cell lymphoma with double hit/triple hit (HGBL-DH/TH) group and high-grade B-cell lymphoma non-specified (HGBL-NOS) group, according to the 2016 version of the World Health Organization (WHO) Hematopoietic and Lymphoid Tissues Cancer Classification. Both groups of patients were treated with stratified chemotherapy by risk according to the CNCL-B-NHL-2017 scheme. The deadline for follow-up was December 31, 2023. All the patients were examined by chromosome fluorescence in situ hybridization (FISH), and the rearrangement of genes MYC, BCL-2 and BCL-6 was confirmed. The clinical and pathological characteristics of patients at disease onset were analyzed, and the therapeutic effects of patients in different clinical stages and risk groups were compared. Survival analysis was drawn by Kaplan Meier method, the log-rank test was used to compare the differences in the cumulative survival rate between different groups, and multivariate Cox regression model was used to identify the prognostic factors. Results: A total of 62 patients were included, with an onset age [M(Q1, Q3)] of 7 (4, 11) years, including 48 males and 14 females. There were 11 (17.7%) patients in stageⅡ, 33(53.2%)patients in stage Ⅲ and 18(29.1%)patients in stage Ⅳ. FISH testing showed that 4 cases (6.5%) were HGBL-DH and 3 (4.8%) were HGBL-TH. The remaining 55 cases (88.7%) were HGBL-NOS, with 18 cases accompanied by MYC rearrangement. There were 7 cases in the HGBL-DH/TH group and 55 cases in the HGBL-NOS group. Thirteen cases (20.9%) were treated with the B1 regimen, 3 cases (4.8%) with B2 regimen, 37 cases (59.6%) with C1 regimen, and 9 cases (14.7%) with the C2 regimen. Forty-eight cases (77.4%) received rituximab therapy at the same time. Five cases (8.0%) progressed during treatment. The follow-up time [M(Q1, Q3)] was 43.5 (36.1, 53.7) months. The complete remission rate was 91.9% (57/62). The 3 year overall survival rate was 93.5% and event-free survival (EFS) rate was 91.9%. The 3-year overall survival rate in the HGBL-NOS group was higher than that in the HGBL-DH/TH group (96.3% vs 71.4%, P=0.011). The 3-year EFS rate of the HGBL-NOS group was higher than that of the HGBL-DH/TH group (94.5% vs 71.4%, P=0.037). In the HGBL-NOS subgroup, the overall survival rate of children with MYC rearrangement was lower (100% vs 88.9%,P=0.039). Multivariate Cox regression analysis showed that central invasion (HR=6.05, 95%CI: 1.96-38.13, P=0.046) was a risk factor for overall survival. Conclusion: CNCL-B-NHL-2017 regimen shows significant effects in the treatment of pediatric HGBL, with a good prognosis.

Blinatumomab for MRD-Negative Acute Lymphoblastic Leukemia in Adults

BackgroundMany older adults with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) have a relapse despite having a measurable residual disease (MRD)–negative complete remission with combination chemotherapy. The addition of blinatumomab, a bispecific T-cell engager molecule that is approved for the treatment of relapsed, refractory, and MRD-positive BCP-ALL, may have efficacy in patients with MRD-negative remission.MethodsIn a phase 3 trial, we randomly assigned patients 30 to 70 years of age with BCR::ABL1-negative BCP-ALL (with :: indicating fusion) who had MRD-negative remission (defined as <0.01% leukemic cells in bone marrow as assessed on flow cytometry) after induction and intensification chemotherapy to receive four cycles of blinatumomab in addition to four cycles of consolidation chemotherapy or to receive four cycles of consolidation chemotherapy alone. The primary end point was overall survival, and relapse-free survival was a secondary end point.ResultsThe data and safety monitoring committee reviewed the results from the third efficacy interim analysis and recommended that they be reported. Complete remission with or without full count recovery was observed in 395 of 488 enrolled patients (81%). Of the 224 patients with MRD-negative status, 112 were assigned to each group. The characteristics of the patients were balanced between the groups. At a median follow-up of 43 months, an advantage was observed in the blinatumomab group as compared with the chemotherapy-only group with regard to overall survival (at 3 years: 85% vs. 68%; hazard ratio for death, 0.41; 95% confidence interval [CI], 0.23 to 0.73; P=0.002), and the 3-year relapse-free survival was 80% with blinatumomab and 64% with chemotherapy alone (hazard ratio for relapse or death, 0.53; 95% CI, 0.32 to 0.87). A higher incidence of neuropsychiatric events was reported in the blinatumomab group than in the chemotherapy-only group.ConclusionsThe addition of blinatumomab to consolidation chemotherapy in adult patients in MRD-negative remission from BCP-ALL significantly improved overall survival. (Funded by the National Institutes of Health and others; E1910 ClinicalTrials.gov number, NCT02003222.)

Effectiveness and Patient Experiences of Rhenium Skin Cancer Therapy for Nonmelanoma Skin Cancer: Interim Results from the EPIC-Skin Study.

Nonmelanoma skin cancer and its treatment represent a significant global cancer burden for health care systems and patients. Rhenium skin cancer therapy (Rhenium SCT) is a novel noninvasive radionuclide nonmelanoma skin cancer treatment, which can be provided in a single outpatient session. The aim of this prospective, multicenter, single-arm, international, phase IV study (EPIC-Skin) is to assess clinic- and patient-reported outcomes of Rhenium SCT as a treatment for basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Methods: Eligible patients had biopsy-proven stage I or stage II BCC or SCC lesions no more than 3 mm deep and no larger than 8 cm2 in area. Rhenium SCT resin was applied to an adhesive foil affixed to the target lesion in a single session. Interim efficacy and safety analysis were planned once 50% of target patients had recorded a 6-mo follow-up visit. Primary outcome is the proportion of lesions achieving complete response using modified RECIST. Secondary and other outcome measures include patient-reported quality of life (QoL), treatment comfort, and cosmesis. Results: A total of 182 patients was enrolled and administered Rhenium SCT (50 Gy dose to deepest point of target) to at least 1 BCC or SCC. Of 81 patients who reached the 6-mo posttreatment follow-up, it was found that 97.2% (103/106) of lesions showed complete responses and 2.8% (3/106) had partial responses. Improvements in QoL were also reported, whereas no patients reported any pain or discomfort during treatment. Adverse events were reported in 15.9% (29/182) of patients and were rated grade 1 (n = 19), grade 2 (n = 9), or grade 3 (n = 1). Conclusion: This preliminary analysis of the EPIC-Skin study indicates that Rhenium SCT is safe and effective for the treatment of BCC and SCC and is associated with significant QoL improvements. It will be particularly beneficial for lesions that are difficult to treat surgically because of size and location. It is also beneficial for patients with comorbidities or those unable to receive conventional fractionated radiotherapy.

Interim results of the randomized phase 2 cohort of study FW-2020-01 assessing the efficacy, safety and pharmacodynamics of CM24 in combination with nivolumab and chemotherapy in advanced/metastatic pancreatic cancer.

LBA4143 Background: The novel monoclonal antibody CM24 blocks the activity of Carcinoembryonic Antigen Cell Adhesion Molecule 1 (CEACAM1), known to have key roles in cancer progression, immune evasion, and metastasis. We present the interim efficacy and safety data from the global multi-center, open label, randomized Phase 2 study (NCT 04731467) in patients (pts) with advanced/metastatic pancreatic ductal adenocarcinoma (PDAC) who progressed after 1st line therapy, treated with CM24, nivolumab (nivo) and chemotherapy vs. chemotherapy (CH). Methods: Patients with advanced/metastatic PDAC progressing after 1 prior line of systemic therapy including fluoropyrimidine/irinotecan or gemcitabine/nab-paclitaxel, having ≥1 measurable lesion, ≥18-year-old, ECOG ≤1 and adequate organ function were randomized 1:1 based on the class of prior CH received. Randomization was either to the experimental groups (EX) receiving CM24 (20mg/kg, q2wk), nivo (240mg/kg, q2wk) with one of the following CH regimens, liposomal irinotecan, 5 fluorouracil and leucovorin (Nal-IRI; q2wk) or gemcitabine/nab-paclitaxel (gem/nab; q1wk x3) or the control groups (C) with one of the CH regimens alone. This is a Bayesian design with an overall planned sample size of 60 pts with Overall Survival (OS) as the primary endpoint. Secondary endpoints include progression free survival (PFS), objective response rate (ORR) and disease control rate (DCR). An interim estimate of PFS HR, ORR and DCR based on data cut-off date of 21 Feb 2024 is reported. The analysis compares the EX vs. the respective C arm using log-rank test stratified by CH regimen. Results: A total of 63 PDAC pts were evenly randomized across the study arms. At data cut-off date, a total of 18 pts, 9 per treatment regimen remain on treatment. The median follow-up time for the Nal-IRI regimen is 6.3 months (95% CI: 5.5-8.4) and 5.2 months (95% CI: 4.0-6.7) for the gem/nab regimen. Median PFS ORR and DCR for the Nal-IRI EX arm were 3.8m (1.9-5.1; HR 0.70; p=0.213), 18.8% and 62.6%, and for the Nal-IRI C arm 1.9m (1.8-5.6), 6.3% and 40%, respectively (Table). Data for the gem/nab regimen and OS data for both regimens are not mature. Overall Grade ≥3 AE rate was 50% in the Nal-IRI EX arm and 13% in the C arm. The most common treatment-emergent grade ≥3 AEs EX vs. C were diarrhea (18.8% vs 6.7%), fatigue (18.8% vs 6.7%) and anemia (6.3% vs 0%). Conclusions: The interim analysis suggests that the combination of CM24/nivo/Nal-IRI/5FU/LV has a manageable safety profile with a longer PFS supported by higher ORR and DCR. OS Data continues to mature and will be reported once available. Clinical trial information: NCT04731467 . [Table: see text]

BEAT-meso: A randomized phase III study of bevacizumab (B) and standard chemotherapy (C) with or without atezolizumab (A), as first-line treatment (TX) for advanced pleural mesothelioma (PM)—Results from the ETOP 13-18 trial.

LBA8002 Background: The currently approved frontline TXs for PM are the combination of ipilimumab/nivolumab or platinum plus pemetrexed. The addition of B to C has been shown to improve overall survival in a randomized clinical trial. While combined immunotherapy or single agent immunotherapy with C is superior to C alone, there is potential for a synergistic triple combination of C, B, and immunotherapy. Methods: BEAT-meso (NCT03762018) is an international open-label, 1:1 randomized phase III trial, stratified by histology and stage. The objective is to determine the efficacy and safety of adding A (1200 mg, Q3W until progression) to B (15mg/kg, Q3W until progression) and standard C (4-6 cycles of carboplatin AUC5 with pemetrexed 500 mg/m2, Q3W), as first-line TX for advanced PM. The trial is designed to detect an increase in the median overall survival (OS, primary endpoint) with the addition of A, aiming for a hazard ratio (HR) of 0.708, at 2.5% 1-sided alpha and 82% power (284 deaths, sample size 400 patients (pts)). In the pre-specified interim efficacy analysis (80% of the events, 01/2023), boundary was not crossed, and the trial continued to completion. Secondary endpoints include progression-free survival (PFS), objective response rate (ORR), disease control rate, duration of response (DoR), adverse events (AEs) assessed by CTCAE v5.0 and symptom-specific and global quality of life (QoL). Results: Between 04/2019 and 03/2022, a total of 400 pts was randomized, 200 per arm. The median age was 70 years, 79% were male, 50% were former smokers, 65% had ECOG performance status 1 and 78% had epithelioid histology. At a median follow-up of 35 months (m) (as of 1/09/2023), median OS was 20.5m [95% CI: 17.5-23.3] in the ABC and 18.1m [15.7-20.9] in the BC arm (deaths: 145 &amp; 150; HRABC vs BC=0.84; [0.66 - 1.06], 2-sided stratified p=0.14, ITT final analysis). PFS was significantly longer in ABC with median 9.2m [8.1-10.9] vs 7.6m [6.9-8.3] in BC (HR=0.72; [0.59 - 0.89], 2-sided stratified p=0.0021). Histology shows a significant TX interaction for both PFS and OS. The OS HR is 0.51 [0.32-0.80] for non-epithelioid and 1.01 [0.77-1.32] for epithelioid (interaction p=0.012). In an exploratory analysis, post-progression OS was significantly different between the two arms, adjusted for post-progression TX (HR=0.76; [0.58 - 0.99]). The ORR was 55% in ABC and 49% in BC (p=0.27), while median DoR was 8.2m [6.8-9.7] in ABC and 5.6m [4.8-7.0] in BC (p=0.0041). Global QoL change was not significantly different between the two arms. Grade≥3 TX-related AEs occurred in 55% of pts in ABC and 47% of pts in BC (grade 5: 7 and 1 pt, respectively). Conclusions: The significant increase in median PFS with the addition of A did not translate into a significant increase in median OS. ABC demonstrated superiority over BC in non-epithelioid cases. Clinical trial information: NCT03762018 .

Interim safety and efficacy of BP1001 in a phase II acute myeloid leukemia (AML) study.

6511 Background: Oncogenic tyrosine kinases induce AML progression via the growth factor receptor bound protein-2 (Grb2). BP1001, a liposome-incorporated Grb2 antisense oligonucleotide,enhanced cancer cell sensitivity to chemotherapy, such as decitabine (DEC) and venetoclax (VEN). A multi-center open-label Phase II study was initiated to assess whether the BP1001 + DEC + VEN combination provides higher response rates than historically reported responses of DEC + VEN in newly diagnosed AML (including secondary AML) (cohort 1) or refractory/relapsed (R/R; cohort 2) AML patients (pts) considered unsuitable for intensive chemotherapy. Per protocol, when 19 evaluable pts are enrolled in each cohort, interim analysis will be performed to determine which cohort has ≥5 complete responses and will continue with enrollment. Methods: BP1001 was given, beginning on Day 4, at 60 mg/m2 IV, 2x weekly for a total of 8 doses over a 28-day cycle. DEC was given IV on days 1 to 5 at 20 mg/m2. VEN was given PO at 100 mg on day 1, 200 mg on day 2, and 400 mg from day 3 to day 14 or 21. Eligible pts were considered unsuitable for or refused intensive chemotherapy and had ECOG performance status of 0-2. Interim analysis was performed on Jan 24, 2024 on pts enrolled between July 28, 2020 and December 26, 2023. Evaluability for efficacy was defined as: completion of at least 4 cycles of combination therapy, documented Progressive Disease (PD) or any drug toxicity at any time, or CR/CRi/CRh prior to 4 cycles. Results: In Cohort 1, 31 newly diagnosed pts were enrolled; 20 evaluable pts (9 male: 45%) with a median age of 75 years (range, 69 - 84), treated with at least 1 cycle of BP1001 + DEC + VEN, had adverse-risk (n=12, ELN 2017 classification) or secondary AML (sAML; n=7) evolved from MDS (n=4), CMML (n=1) or treatment-related AML (n=2). Fifteen pts (75% of evaluable; 54% of enrolled) achieved CR/CRi/CRh; 2 pts achieved partial remission (PR) and 2 achieved stable disease (SD). In Cohort 2, 38 R/R pts were enrolled; 23 evaluable pts (13 male: 57%) with a median age of 63 years (range, 24 - 89), treated with at least 1 cycle of BP1001 + DEC + VEN, had adverse-risk (n=13) or sAML (n=5). Twelve pts (55% of evaluable; 32% of enrolled) achieved CR/CRi/CRh; 1 pt achieved PR, 8 achieved SD and 1 had treatment failure. Among the evaluable pts of both cohorts, adverse events were consistent with those expected with DEC, VEN and/or AML, including fatigue (72%), anemia (60%) and neutropenia (49%), while the most frequent serious adverse events were febrile neutropenia (26%) and sepsis (5%). Conclusions: BP1001 + DEC + VEN has been safely administered to pts without drug-related toxicity. Since &gt;5 responses are observed in both cohorts, the study will continue with enrollment up to 98 and 54 evaluable pts in cohorts 1 and 2, respectively. Efficacy data are encouraging in a challenging population of frontline adverse-risk, sAML and R/R pts. Clinical trial information: NCT02781883 .

FURTHER: A global study to evaluate furmonertinib in patients with EGFR mutant NSCLC including uncommon EGFR mutations (FURMO-002).

TPS8666 Background: Furmonertinib (AST2818) is an oral, highly brain-penetrant, and broadly active mutation-selective epidermal growth factor receptor ( EGFR) inhibitor engineered for broad activity and selectivity across EGFRmutations (mts) (1). Furmonertinib is approved in China for first-line advanced NSCLC with EGFR Ex19del or L858R mts based on the progression-free survival benefit observed in the Phase 3 study versus gefitinib (FURLONG). Furmonertinib has also demonstrated promising interim efficacy and safety in patients (pts) with NSCLC harboring EGFR exon 20 insertion (ex20ins) mts with a confirmed overall response rate (ORR) of 78.6% (n=28) by blinded independent central review (BICR) and a preliminary median duration of response (DoR) of 15.2 months in the front-line setting (FAVOUR study; see Han et al., WCLC 2023). Furmonertinib recently obtained FDA Breakthrough Therapy Designation for the treatment of pts with advanced NSCLC with EGFR ex20ins mts. P-loop and αC-helix Compressing (PACC) mts represent another subset of uncommon EGFR mts (2) that are similar to ex20ins mts in narrowing the drug-binding pocket; including G719X, S768I, E709X, L747X, V774M. Preclinical data indicating that furmonertinib is potent in models harboring EGFR PACC mts Developing efficacious, well-tolerated, and CNS-penetrant medicines for NSCLC pts with EGFR ex20ins mts and PACC mts remains an unmet need. Methods: FURTHER (FURMO-002) is the first global trial evaluating furmonertinib in NSCLC pts with EGFR and HER2 mts in North America, Europe, and the Asia-Pacific. FURTHER is a phase 1b, open-label, multicenter study in which pts will be treated orally with furmonertinib daily. For Stage 1 dose-escalation, the primary endpoint is incidence and severity of adverse events, including dose limiting toxicities and has been completed. For Stage 2 dose expansion, approximately 120 pts will be enrolled across 4 expansion cohorts. Stage 2 Cohorts 1-3 dose expansion cohorts will enroll pts with previously treated, locally advanced or metastatic NSCLC pts with either EGFR ex20ins mts, HER2 ex20ins mts, or EGFR activating mts, respectively. Cohorts 1-3 allow enrollment of pts with prior EGFR or HER2-directed therapy. Stage 2 Cohort 4 will enroll EGFR TKI-naïve NSCLC pts with EGFR PACC mts. Key inclusion criteria include documented EGFR or HER2 mts by local testing and measurable disease per RECIST v1.1. Stage 2 primary endpoint is ORR using RECIST v1.1. Key secondary endpoints include progression-free survival and overall survival. Stage 2 enrollment is ongoing. 1. Musib et al., NACLC 2022. 2. Robichaux et al., 2021. Clinical trial information: NCT05364073 .

Toripalimab (anti-PD-1) plus recombinant human endostatin as adjuvant therapy in patients with resected stage III melanoma: Interim analysis of an open-label phase II trial.

e21557 Background: Patients with completely resected stage III melanoma are under high risk of disease recurrence. Recurrence-free survival (RFS) remains unsatisfactory despite there is adjuvant anti-PD-1 monotherapy following surgery, with the 1-year RFS about 70% and 2-year RFS about 49% in our country. It's urgent to explore combined regimens with anti-PD-1 to further improve the RFS. Here we report the interim efficacy and safety results of toripalimab (a PD-1 inhibitor) plus recombinant human endostatin (an angiogenesis inhibitor) as combined adjuvant therapy for patients with resected stage III melanoma. Methods: This prospective single-center, single-arm, open-label phase II trial screened adult patients with stage III melanoma who had undergone complete tumor resection within the previous 13 weeks for eligibility. Toripalimab was administrated in intravenous drip to patients at 3 mg/kg every 2 weeks in a 4-week cycle (day 1 and day 15 of each cycle), for up to 13 cycles or until disease recurrence, unacceptable toxicity or decease. Recombinant human endostatin was administrated in a continuous intravenous infusion at a dose of 210 mg from day 1 to day 3 for each 4-week cycle, for up to 6 cycles or until disease recurrence, unacceptable toxicity or decease. The primary endpoints were the 1-year and 2-year RFS. Results: By the data cut-off on Jan 25, 2024, 43 eligible patients with resected stage III melanoma between October 2021 and December 2023 were enrolled. In ITT population (n = 43), patients' median age was 56 (IQR 52~69) years. There were 25 (58%) male and 18 (42%) female; 27 (63%) with acral melanoma and 16 (37%) with cutaneous melanoma. With a median follow-up of 14 months, the 1-year and 2-year RFS rates were 83% and 71%, respectively. For security, 33 (77%) patients experienced at least one adverse event (AE), including 27 grade 1-2 AEs and 6 grade 3~4 AEs. One patient discontinued the combined therapy due to immunotherapy-associated myocarditis. Conclusions: Toripalimab in combination with recombinant human endostatin as adjuvant therapy could further improve disease-free survival in Chinese patients with completely resected stage III melanoma, with a manageable toxicity profile. Clinical trial information: 05907512 .

A phase 3 global study of telisotuzumab vedotin versus docetaxel in previously treated patients with c-Met 0verexpressing, EGFR wildtype, locally advanced/metastatic nonsquamous NSCLC (TeliMET NSCLC-01).

TPS8656 Background: Non-small cell lung cancer (NSCLC) encompasses over two-thirds of lung cancer diagnoses, most presenting as advanced disease. c-Met (MET protein) is overexpressed in NSCLC. In this study, we investigate telisotuzumab vedotin (Teliso-V), a first-in-class antibody-drug conjugate composed of a c-Met–targeting antibody (telisotuzumab) and a microtubule polymerization inhibitor (cytotoxin monomethyl auristatin E). Interim efficacy analysis of the Phase 2 LUMINOSITY study (NCT03539536) of Teliso-V monotherapy showed an objective response rate (ORR) of 37% (95% CI: 24–51) in previously treated patients (pts) with c-Met overexpressing epidermal growth factor receptor (EGFR) wildtype (WT) nonsquamous NSCLC and 52% (95% CI: 31–73) in the high c-Met overexpressing group (Camidge DR et al. J Clin Oncol. 2022;40(16_suppl):9016). Methods: This randomized, open-label, global Phase 3 study (NCT04928846) evaluates the efficacy, safety, pharmacokinetics, and pharmacodynamics of Teliso-V monotherapy compared with docetaxel in pts with locally advanced/metastatic c-Met overexpressing EGFR WT nonsquamous NSCLC who have progressed on prior therapy. Enrollment began in May 2022. To be eligible across global sites, pts must be ≥18 years old with c-Met overexpressing (ie, ≥25% tumor cells at 3+ intensity by IHC assay [anti-MET clone SP44; Roche Tissue Diagnostics]) locally advanced/metastatic EGFR WT NSCLC, with ECOG score ≤1. Pts must have progressed on at least one prior line of therapy, which can include no more than one line of prior chemotherapy, and must be naïve to c-Met–targeted antibodies and docetaxel. Target enrollment is 698 pts. Pts will be randomized 1:1 to Teliso-V (1.9 mg/kg every 2 weeks) and docetaxel (control, 75 mg/m2 every 3 weeks). Treatment continues until disease progression or discontinuation criteria are met. Co-primary endpoints are progression-free survival by independent central review and overall survival. Secondary endpoints include ORR, duration of response, and patient-reported outcomes. Safety, adverse events (AEs), drug discontinuation or dosing modification due to AEs, and tolerability will be assessed. Previously presented at the 2023 ESMO Congress, Final Publication Number: 1501TiP, Antonio Lugini et al. - Reused with permission. Clinical trial information: NCT04928846 .

A phase 2 trial of IO102-IO103 and nivolumab-relatlimab fixed-dose combination in previously untreated, unresectable melanoma.

TPS9605 Background: One emerging strategy to augment immune checkpoint inhibitor efficacy is to eliminate immunosuppressive cell populations in the tumor microenvironment (TME) through vaccination. IO102-IO103 is an investigational cancer vaccine that targets both tumor and immune-suppressive cells in the TME. IO102-IO103 treatment promotes inflammation and potentiates anti-tumor activity via activation and expansion of T cells against IDO1 and/or PD-L1 positive cells. IO102-IO103 plus nivolumab demonstrated an impressive objective response rate (ORR) of 80% in the phase 1/2 MM1636 trial of 30 patients with previously untreated, unresectable melanoma, and a randomized phase 3 trial of pembrolizumab with or without IO102-IO103 (NCT05155254) is ongoing. No prior studies have evaluated IO102-IO103 in combination with dual PD-1 and LAG-3 blockade with nivolumab-relatlimab (nivo-rela), and to our knowledge there are no existing clinical data for other investigational agents in combination with nivo-rela. Methods: NCT05912244 is a single-arm, investigator-initiated trial testing IO102-IO103 in combination with nivo-rela in patients with previously untreated, unresectable melanoma. Twelve of forty-three planned patients have been enrolled. All patients will be treated with nivo-rela every four weeks for up to two years. IO102-IO103 will be administered subcutaneously every two weeks for the initial eight weeks, and then every four weeks for up to two years. An interim efficacy analysis for futility will be performed after response data are available for 21 patients. Eligible patients must have histologically confirmed, unresectable stage III or stage IV non-uveal melanoma, measurable disease by RECIST v1.1, an ECOG performance status of 0 or 1, and definitive treatment of any brain metastases. Prior systemic treatment in the neoadjuvant or adjuvant setting is allowed if completed at least six months prior to trial enrollment. Available pre-treatment melanoma tissue is required, and all patients will undergo an on-treatment study biopsy between the second and third dose of nivo-rela. Peripheral blood mononuclear cells will be collected prior to the first three doses of nivo-rela. The primary endpoint is ORR by RECIST v1.1, weighted by PD-L1 expression. Secondary endpoints include safety assessed by Common Terminology Criteria for Adverse Events v 5.0, progression-free survival (PFS) by RECIST v1.1, duration of disease response, and disease control rate. Exploratory correlative endpoints include assessment of changes in PD-L1 and IDO-expressing cells in the TME on paired tumor biopsies, identification of peripheral PD-L1 and IDO-reactive cells in the peripheral blood by ELISpot, and assessment of peripheral pre-treatment and on-treatment T cell clonality by TCR sequencing. Clinical trial information: NCT05912244 .

Abstract PO5-19-08: Neoadjuvant HER2-targeted Therapy +/- Immunotherapy with Pembrolizumab (neoHIP): An Open Label Randomized Phase II Trial

Abstract Background: Immune checkpoint inhibition (ICI) is synergistic with HER2-directed therapy in pre-clinical models. Clinically, pembrolizumab (K)-mediated ICI plus HER2-directed therapy with trastuzumab (H) was safe and demonstrated modest activity in H-resistant HER2-positive (HER2+) metastatic breast cancer. Because ICI may confer more robust activity when administered earlier in the course of disease, H and K administered in the curative-intent, treatment-naive setting may allow for de-escalation of cytotoxics; confer life-long, tumor-specific immunity; and ultimately, improve cure rates. Moreover, the synergy of H and K with paclitaxel (T) may overcome the need for dual HER2-blockade with H plus pertuzumab (P). In this randomized, multicenter, phase II, open-label trial the efficacy and safety of neoadjuvant THP vs THP-K vs TH-K are explored. Methods: Patients (pts) ≥18y with previously untreated, stage II-III, HER2+ breast cancer are being randomized and stratified by clinical nodal status (positive vs. negative) and hormone receptor status (positive vs. negative). In arm A, pts receive T at 80mg/m2 weekly for 12 weeks, H at 8mg/Kg (loading dose) and then 6mg/Kg every 3 weeks x 3 doses, P at 840 mg (loading dose) and then 420mg/Kg every 3 weeks x 3 doses (THP). In arm B, pts receive THP plus K at 200mg every 3 weeks x 4 doses (THP-K). In arm C, pts receive TH-K. After enrollment of 22 pts to arm C, a prespecified interim efficacy analysis was conducted, and enrollment to this arm was subsequently terminated. Enrollment to the other arms continues with 32/58 pts enrolled to arm A and 33/58 pts enrolled to arm B as of 2/14/2023. Definitive surgery is 3-6 weeks after the last dose. After surgery, pts are treated per the treating physician’s discretion per local clinical standard. The primary end point is pathologic complete response (pCR) rate in the breast and axilla (ypT0/Tis ypN0). Secondary end points include pCR rate by ypT0ypN0 and ypT0/Tis, residual cancer burden index, event free survival, breast conserving surgery rate, safety and overall survival. Exploratory correlative studies will characterize potential immune biomarkers predictive of efficacy and/or toxicity. Funding sources: BCRF, Merck NCT03747120 Citation Format: Heather McArthur, Jorge Henrique Santos Leal, Isaac Chan, Nisha Unni, Stephen Shiao, Joshua Gruber, Samira Syed, Namrata Peswani, Navid Sadeghi, Glenda Delgado, Dawn Klemow, Reva Basho, Meredith Carter, Mai Badran, Nasir Qureshi, Jessica Curtin, Joshua Weese, Stephanie Rice, Michelle Phillips, David Chan, Hugo Hool, Dorothy Park, Mary El-Masry, Philomena McAndrew, Swati Sikaria, Laura Spring, Aditya Bardia, Mourad Tighiouart, Farnaz Dadmanesh, Armando Giuliano, Katherine Sanchez, David Page. Neoadjuvant HER2-targeted Therapy +/- Immunotherapy with Pembrolizumab (neoHIP): An Open Label Randomized Phase II Trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-19-08.

Interim Long-term Safety and Efficacy of XEN1101, a Potent, Selective Potassium Channel Opener: Update from an Ongoing Open-label Extension of a Phase 2b Study (X-TOLE) in Adults with Focal Epilepsy (S19.005)

Interim Long-term Safety and Efficacy of XEN1101, a Potent, Selective Potassium Channel Opener: Update from an Ongoing Open-label Extension of a Phase 2b Study (X-TOLE) in Adults with Focal Epilepsy (S19.005)