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Camrelizumab Combined with FOLFOX4 Regimen as First-Line Therapy for Advanced Hepatocellular Carcinomas: A Sub-Cohort of a Multicenter Phase Ib/II Study.
Li, H, Qin, S, Liu, Y, Chen, Z, Ren, Z, Xiong, J, Meng, Z, Zhang, X, Wang, L, Zhang, X, et al
Drug design, development and therapy. 2021;:1873-1882
Abstract
BACKGROUND Immune checkpoint inhibitors and chemotherapy can synergistically increase efficacy in a variety of malignancies. We conducted this phase Ib/II study to assess the safety and efficacy of anti-PD-1 antibody camrelizumab in combination with FOLFOX4 for treatment-naive advanced hepatocellular carcinoma (aHCC). METHODS This open-label, multicenter phase Ib/II study (NCT03092895) enrolled patients with aHCC and without prior systemic treatment for treatment with camrelizumab (3 mg/kg) and FOLFOX4 every two weeks. First, six patients were enrolled, followed by an additional 28 patients after dose-limiting toxicity cases were determined to be <33% of patients. The primary endpoint was tolerability and safety of treatment. RESULTS A total of 34 aHCC patients were enrolled and received study treatment. No dose-limiting toxicity were observed in the first six patients enrolled. Twenty-nine (85.3%) of the total 34 patients had grade ≥3 treatment-related adverse events (TRAEs), with the most common ones being decreased neutrophil count (55.9%) and decreased white blood cell count (38.2%). No TRAEs-related deaths occurred. The objective response and disease control rate were 29.4% (95% CI, 15.1-47.5) and 79.4% (95% CI, 62.1-91.3), respectively. The median duration of response, progression-free survival, and overall survival was 6.9 months (range, 3.3-11.5), 7.4 months (95% CI, 3.9-9.2), and 11.7 months (95% CI, 8.2-22.0), respectively. CONCLUSION Camrelizumab combined with FOLFOX4 for first-line treatment of patients with aHCC showed good safety and tolerability, with promising preliminary antitumor activity.
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A multi-center, single-arm, phase Ib study of pembrolizumab (MK-3475) in combination with chemotherapy for patients with advanced colorectal cancer: HCRN GI14-186.
Herting, CJ, Farren, MR, Tong, Y, Liu, Z, O'Neil, B, Bekaii-Saab, T, Noonan, A, McQuinn, C, Mace, TA, Shaib, W, et al
Cancer immunology, immunotherapy : CII. 2021;(11):3337-3348
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Abstract
Modified FOLFOX6 is an established therapy for patients with metastatic colorectal cancer (mCRC). We conducted a single-arm phase Ib study to address the hypothesis that addition of pembrolizumab to this regimen could safely and effectively improve patient outcomes (NCT02375672). The relationship between immune biomarkers and clinical response were assessed in an exploratory manner. Patients with mCRC received concurrent pembrolizumab and modified FOLFOX6. The study included safety run-in for the first six patients. The primary objective was median progression-free survival (mPFS), with secondary objectives including median overall survival, safety, and exploratory assessment of immune changes. To assess immunological impact, peripheral blood was collected at baseline and during treatment. The levels of soluble factors were measured via bioplex, while a panel of checkpoint molecules and phenotypically defined cell populations were assessed with flow cytometry and correlated with RECIST and mPFS. Due to incidences of grade 3 and grade 4 neutropenia in the safety lead-in, the dose of mFOLFOX6 was reduced in the expansion cohort. Median PFS was 8.8 months and median OS was not reached at data cutoff. Best responses of stable disease, partial response, and complete response were observed in 43.3%, 50.0%, and 6.7% of patients, respectively. Several soluble and cellular immune biomarkers were associated with improved RECIST and mPFS. Immunosuppressive myeloid and T cell subsets that were analyzed were not associated with response. Primary endpoint was not superior to historic control. Biomarkers that were associated with improved response may be informative for future regimens combining chemotherapy with immune checkpoint inhibitors.
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Molecular correlates of response to eribulin and pembrolizumab in hormone receptor-positive metastatic breast cancer.
Keenan, TE, Guerriero, JL, Barroso-Sousa, R, Li, T, O'Meara, T, Giobbie-Hurder, A, Tayob, N, Hu, J, Severgnini, M, Agudo, J, et al
Nature communications. 2021;(1):5563
Abstract
Immune checkpoint inhibitors (ICIs) have minimal therapeutic effect in hormone receptor-positive (HR+ ) breast cancer. We present final overall survival (OS) results (n = 88) from a randomized phase 2 trial of eribulin ± pembrolizumab for patients with metastatic HR+ breast cancer, computationally dissect genomic and/or transcriptomic data from pre-treatment tumors (n = 52) for molecular associations with efficacy, and identify cytokine changes differentiating response and ICI-related toxicity (n = 58). Despite no improvement in OS with combination therapy (hazard ratio 0.95, 95% CI 0.59-1.55, p = 0.84), immune infiltration and antigen presentation distinguished responding tumors, while tumor heterogeneity and estrogen signaling independently associated with resistance. Moreover, patients with ICI-related toxicity had lower levels of immunoregulatory cytokines. Broadly, we establish a framework for ICI response in HR+ breast cancer that warrants diagnostic and therapeutic validation. ClinicalTrials.gov Registration: NCT03051659.
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Distinct Gene Expression Signatures Characterize Strong Clinical Responders Versus Nonresponders to Canakinumab in Children With Systemic Juvenile Idiopathic Arthritis.
Verweyen, EL, Pickering, A, Grom, AA, Schulert, GS
Arthritis & rheumatology (Hoboken, N.J.). 2021;(7):1334-1340
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Abstract
OBJECTIVE Canakinumab is a human anti-interleukin-1β (anti-IL-1β) blocking agent that effectively neutralizes IL-1β-mediated signaling for treatment of systemic juvenile idiopathic arthritis (JIA). While many patients have dramatic clinical response to IL-1 blockade, approximately one-third fail to respond, but there are currently no validated clinical or immunologic predictors of response. We undertook this study to characterize distinct gene signatures for treatment response and nonresponse to canakinumab in systemic JIA patients. METHODS We performed a secondary analysis of whole-blood gene expression microarrays using blood samples obtained from healthy controls and systemic JIA patients at baseline and on day 3 after canakinumab treatment (GEO accession no. GSE80060). Patients were considered strong clinical responders if they met the ACR90 response (exhibited ≥90% improvement in the American College of Rheumatology [ACR] JIA response criteria; nonresponders were those who met ACR30 [exhibiting ≤30% improvement in the ACR JIA response criteria]). A random-effects model with patient identity as the random variable was used for differential expression analysis. RESULTS We identified a distinct gene expression signature in patients with a strong clinical response to canakinumab treatment as compared to nonresponders, mediated by up-regulation of neutrophil- and IL-1-associated genes and characterized by increasing divergence from control transcriptomes with increasing clinical response. We also identified a signature including up-regulated CD163 expression that was associated with canakinumab nonresponse. Intriguingly, canakinumab treatment induced either up- or down-regulation of type I interferon (IFN) genes, independent of clinical response. CONCLUSION Here, we identify a gene signature in systemic JIA patients prior to receiving treatment that distinguishes strong responders to canakinumab from nonresponders. Further prospective studies are needed to assess the utility of these insights for treatment decisions in systemic JIA and to track the association of up-regulated type I IFN signatures with systemic JIA complications.
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Fecal microbiota transplant overcomes resistance to anti-PD-1 therapy in melanoma patients.
Davar, D, Dzutsev, AK, McCulloch, JA, Rodrigues, RR, Chauvin, JM, Morrison, RM, Deblasio, RN, Menna, C, Ding, Q, Pagliano, O, et al
Science (New York, N.Y.). 2021;(6529):595-602
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Anti-programmed cell death protein 1 (PD-1) therapy provides long-term clinical benefits to patients with advanced melanoma. The composition of the gut microbiota correlates with anti-PD-1 efficacy in preclinical models and cancer patients. To investigate whether resistance to anti-PD-1 can be overcome by changing the gut microbiota, this clinical trial evaluated the safety and efficacy of responder-derived fecal microbiota transplantation (FMT) together with anti-PD-1 in patients with PD-1-refractory melanoma. This combination was well tolerated, provided clinical benefit in 6 of 15 patients, and induced rapid and durable microbiota perturbation. Responders exhibited increased abundance of taxa that were previously shown to be associated with response to anti-PD-1, increased CD8+ T cell activation, and decreased frequency of interleukin-8-expressing myeloid cells. Responders had distinct proteomic and metabolomic signatures, and transkingdom network analyses confirmed that the gut microbiome regulated these changes. Collectively, our findings show that FMT and anti-PD-1 changed the gut microbiome and reprogrammed the tumor microenvironment to overcome resistance to anti-PD-1 in a subset of PD-1 advanced melanoma.
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Pembrolizumab in vaginal and vulvar squamous cell carcinoma: a case series from a phase II basket trial.
How, JA, Jazaeri, AA, Soliman, PT, Fleming, ND, Gong, J, Piha-Paul, SA, Janku, F, Stephen, B, Naing, A
Scientific reports. 2021;(1):3667
Abstract
Vaginal and vulvar squamous cell carcinoma (SCC) are rare tumors that can be challenging to treat in the recurrent or metastatic setting. We present a case series of patients with vaginal or vulvar SCC who were treated with single-agent pembrolizumab as part of a phase II basket clinical trial to evaluate efficacy and safety. Two cases of recurrent and metastatic vaginal SCC, with multiple prior lines of systemic chemotherapy and radiation, received pembrolizumab. One patient had significant reduction (81%) in target tumor lesions prior to treatment discontinuation at cycle 10 following confirmed progression of disease with new metastatic lesions (stable disease by irRECIST criteria). In contrast, the other patient with vaginal SCC discontinued treatment after cycle 3 due to disease progression. Both patients had PD-L1 positive vaginal tumors and tolerated treatment well. One case of recurrent vulvar SCC with multiple surgical resections and prior progression on systemic carboplatin had a 30% reduction in her target tumor lesions following pembrolizumab treatment with a PD-L1 positive tumor. Treatment was discontinued for grade 3 mucositis after cycle 5. Pembrolizumab may provide some clinical benefit to some patients with vaginal or vulvar SCC and is overall safe to utilize in this population. Future studies are needed to evaluate the efficacy of pembrolizumab in these rare tumor types and to identify predictive biomarkers of response.
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PCSK9 inhibition with alirocumab in pediatric patients with heterozygous familial hypercholesterolemia: The ODYSSEY KIDS study.
Daniels, S, Caprio, S, Chaudhari, U, Manvelian, G, Baccara-Dinet, MT, Brunet, A, Scemama, M, Loizeau, V, Bruckert, E
Journal of clinical lipidology. 2020;(3):322-330.e5
Abstract
BACKGROUND Heterozygous familial hypercholesterolemia (HeFH) is a genetic disorder characterized by elevated levels of low-density lipoprotein cholesterol (LDL-C). OBJECTIVE This phase 2 dose-finding study (NCT02890992) evaluated the efficacy, safety, and dose selection of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor alirocumab in pediatric HeFH patients. METHODS HeFH patients (n = 42) who were aged 8-17 years, had body weight (BW) ≥25 kg, and had LDL-C ≥130 mg/dL despite optimal statin/other lipid-modifying therapies were enrolled in 4 cohorts according to BW: cohort #1: 30 mg (<50 kg) or 50 mg (≥50 kg) every 2 weeks (Q2W), #2: 40 mg (<50 kg) or 75 mg (≥50 kg) Q2W, #3: 75 mg (<50 kg) or 150 mg (≥50 kg) every 4 weeks (Q4W), #4: 150 mg (<50 kg) or 300 mg (≥50 kg) Q4W. Primary endpoint was LDL-C % change from baseline to week 8. RESULTS Mean age was 12.4 years and 95% of patients were on a statin. Baseline LDL-C levels were 160.0-188.9 mg/dL and free PCSK9 was 186.4-201.7 ng/mL across the cohorts. At week 8, the higher dose cohorts (2 and 4) demonstrated the greatest reductions in LDL-C (-46% and -45%, respectively). Free PCSK9 levels were lowest at week 8 in cohorts 2 and 4 (42.2 ng/mL and 8.6 ng/mL, respectively). Adverse events were reported in 50-90% of patients across the cohorts, and 2 patients discontinued due to adverse events. CONCLUSIONS In pediatric HeFH patients, LDL-C reductions were greatest in the higher dose cohorts. Alirocumab was generally well tolerated at all doses.
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AtezoTRIBE: a randomised phase II study of FOLFOXIRI plus bevacizumab alone or in combination with atezolizumab as initial therapy for patients with unresectable metastatic colorectal cancer.
Antoniotti, C, Borelli, B, Rossini, D, Pietrantonio, F, Morano, F, Salvatore, L, Lonardi, S, Marmorino, F, Tamberi, S, Corallo, S, et al
BMC cancer. 2020;(1):683
Abstract
BACKGROUND Immune checkpoint inhibitors (ICIs) reported remarkable achievements in several solid tumours. However, in metastatic colorectal cancer (mCRC) promising results are limited to patients with deficient mismatch repair/microsatellite instability-high (dMMR/MSI-high) tumours due to their immune-enriched microenvironment. Combining cytotoxic agents and bevacizumab in mCRC with proficient mismatch repair/microsatellite stability (pMMR/MSS) could make ICIs efficacious by increasing the exposure of neoantigens, especially with highly active chemotherapy regimens, inducing immunogenic cell death, increasing the tumoral infiltration of CD8+ T-cells and reducing tumour-associated myeloid-derived suppressor cells. VEGF-blockade also plays an immunomodulatory role by inhibiting the expansion of T regulatory lymphocytes. Consistently with this rationale, a phase Ib study combined the anti-PDL-1 atezolizumab with FOLFOX/bevacizumab as first-line treatment of mCRC, irrespective of microsatellite status, and reported interesting activity and efficacy results, without safety concerns. Phase III trials led to identify FOLFOXIRI plus bevacizumab as an upfront therapeutic option in selected mCRC patients. Drawing from these considerations, the combination of atezolizumab with an intensified upfront treatment (FOLFOXIRI) and bevacizumab could be worthy of investigation. METHODS AtezoTRIBE is a prospective, open label, phase II, comparative trial in which initially unresectable and previously untreated mCRC patients, irrespective of microsatellite status, are randomized in a 1:2 ratio to receive up to 8 cycles of FOLFOXIRI/bevacizumab alone or in combination with atezolizumab, followed by maintenance with bevacizumab plus 5-fluoruracil/leucovorin with or without atezolizumab according to treatment arm until disease progression. The primary endpoint is PFS. Assuming a median PFS of 12 months for standard arm, 201 patients should be randomized in a 1:2 ratio to detect a hazard ratio of 0.66 in favour of the experimental arm. A safety run-in phase including the first 6 patients enrolled in the FOLFOXIRI/bevacizumab/atezolizumab arm was planned, and no unexpected adverse events or severe toxicities were highlighted by the Safety Monitoring Committee. DISCUSSION The AtezoTRIBE study aims at assessing whether the addition of atezolizumab to an intensified chemotherapy plus bevacizumab might be an efficacious upfront strategy for the treatment of mCRC, irrespective of the microsatellite status. TRIAL REGISTRATION AtezoTRIBE is registered at Clinicaltrials.gov ( NCT03721653 ), October 26th, 2018 and at EUDRACT (2017-000977-35), Februray 28th, 2017.
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Efficacy and Safety of Alirocumab in Adults With Homozygous Familial Hypercholesterolemia: The ODYSSEY HoFH Trial.
Blom, DJ, Harada-Shiba, M, Rubba, P, Gaudet, D, Kastelein, JJP, Charng, MJ, Pordy, R, Donahue, S, Ali, S, Dong, Y, et al
Journal of the American College of Cardiology. 2020;(2):131-142
Abstract
BACKGROUND Homozygous familial hypercholesterolemia (HoFH) is characterized by extremely elevated low-density lipoprotein-cholesterol (LDL-C) levels and early onset atherosclerotic cardiovascular disease despite treatment with conventional lipid-lowering treatment. OBJECTIVES This study was designed to assess LDL-C reduction with the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab in adult patients with HoFH. METHODS This randomized, double-blind, placebo-controlled, parallel-group, phase 3 study evaluated efficacy and safety of alirocumab 150 mg every 2 weeks. The primary endpoint was percent reduction from baseline in LDL-C versus placebo after 12 weeks of treatment. RESULTS Patients (N = 69) were randomized 2:1 to alirocumab or placebo. At baseline, background lipid-lowering treatment included 67 patients receiving statin (59 patients on high-intensity statin); 50 patients on ezetimibe; 10 patients on lomitapide; and 10 patients undergoing apheresis. Mean baseline LDL-C was 259.6 mg/dl in the placebo group and 295.0 mg/dl in the alirocumab group. At week 12, the least squares mean difference in LDL-C percent change from baseline was -35.6% (alirocumab [-26.9%] vs. placebo [8.6%]; p < 0.0001). Reductions (least squares mean difference) in other atherogenic lipids at week 12 were: apolipoprotein B, -29.8%; non-high-density lipoprotein cholesterol, -32.9%; total cholesterol, -26.5%; and lipoprotein(a), -28.4% (all p < 0.0001). No serious adverse events, permanent treatment discontinuations, or deaths due to treatment-emergent adverse events were reported during the double-blind treatment period. CONCLUSIONS In the largest randomized controlled interventional trial in HoFH patients to date, alirocumab resulted in significant and clinically meaningful reductions in LDL-C at week 12. Alirocumab was generally well tolerated, with a safety profile comparable to that of placebo. (Study in Participants With Homozygous Familial Hypercholesterolemia [HoFH] [ODYSSEY HoFH] NCT03156621.).
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Evolocumab Effects on Lipoproteins, Measured by High-Performance Liquid Chromatography.
Masuda, D, Kiyosue, A, Hirayama, A, Shimauchi, J, López, JAG, Miyawaki, K, Yamashita, S
Journal of atherosclerosis and thrombosis. 2020;(11):1183-1207
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AIMS: Profiling of lipoproteins can predict risk of cardiovascular disease; gel permeation high-performance liquid chromatography (HPLC) improves prediction accuracy by providing detailed data for specific lipoprotein subclasses. This study applied HPLC to examine the effects of evolocumab, which effectively treats hyperlipidemia and mixed dyslipidemia, on lipoprotein subclasses, specifically the number and size of lipoprotein particles. METHODS This post-hoc analysis used patient blood samples from YUKAWA-2, a phase 3 trial evaluating the efficacy of evolocumab in Japanese adult patients with hyperlipidemia or mixed dyslipidemia and at high risk for cardiovascular disease. We used HPLC to assess observed values and percent change from baseline in cholesterol and triglyceride (TG) concentrations, number of particles in lipoprotein subclasses to week 12, and mean observed values and mean percent change from baseline in variables to weeks 10 and 12. HPLC was also compared with conventional methods in assessing low-density lipoprotein (LDL) cholesterol (LDL-C) values. RESULTS Data for all 404 patients were analyzed. Evolocumab significantly decreased cholesterol and TG concentrations, and total particle count, in very low-density lipoprotein (VLDL) and LDL subclasses. Particle size increased slightly in LDL, high-density lipoprotein (HDL), and VLDL, but data varied widely. At very low LDL-C, HPLC measurements were higher than those from conventional methods. CONCLUSION This research used HPLC to assess the effects of evolocumab in 20 lipid subclasses. By lowering lipid content and improving the lipid profile, evolocumab may reduce atherogenicity. This reduction is better quantified by HPLC than by conventional methods in the very low LDL-C range.