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The New England Journal of Medicine Dec 2023Tebentafusp, a T-cell receptor-bispecific molecule that targets glycoprotein 100 and CD3, is approved for adult patients who are positive for HLA-A*02:01 and have... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Tebentafusp, a T-cell receptor-bispecific molecule that targets glycoprotein 100 and CD3, is approved for adult patients who are positive for HLA-A*02:01 and have unresectable or metastatic uveal melanoma. The primary analysis in the present phase 3 trial supported a long-term survival benefit associated with the drug.
METHODS
We report the 3-year efficacy and safety results from our open-label, phase 3 trial in which HLA-A*02:01-positive patients with previously untreated metastatic uveal melanoma were randomly assigned in a 2:1 ratio to receive tebentafusp (tebentafusp group) or the investigator's choice of therapy with pembrolizumab, ipilimumab, or dacarbazine (control group), with randomization stratified according to the lactate dehydrogenase level. The primary end point was overall survival.
RESULTS
At a minimum follow-up of 36 months, median overall survival was 21.6 months in the tebentafusp group and 16.9 months in the control group (hazard ratio for death, 0.68; 95% confidence interval, 0.54 to 0.87). The estimated percentage of patients surviving at 3 years was 27% in the tebentafusp group and 18% in the control group. The most common treatment-related adverse events of any grade in the tebentafusp group were rash (83%), pyrexia (76%), pruritus (70%), and hypotension (38%). Most tebentafusp-related adverse events occurred early during treatment, and no new adverse events were observed with long-term administration. The percentage of patients who discontinued treatment because of adverse events continued to be low in both treatment groups (2% in the tebentafusp group and 5% in the control group). No treatment-related deaths occurred.
CONCLUSIONS
This 3-year analysis supported a continued long-term benefit of tebentafusp for overall survival among adult HLA-A*02:01-positive patients with previously untreated metastatic uveal melanoma. (Funded by Immunocore; IMCgp100-202 ClinicalTrials.gov number, NCT03070392; EudraCT number, 2015-003153-18.).
Topics: Adult; Humans; Antineoplastic Combined Chemotherapy Protocols; HLA-A Antigens; Melanoma; Uveal Neoplasms; Recombinant Fusion Proteins
PubMed: 37870955
DOI: 10.1056/NEJMoa2304753 -
Cancer Research Aug 2023ARID1A is a subunit of SWI/SNF chromatin remodeling complexes and is mutated in many types of human cancers, especially those derived from endometrial epithelium,...
UNLABELLED
ARID1A is a subunit of SWI/SNF chromatin remodeling complexes and is mutated in many types of human cancers, especially those derived from endometrial epithelium, including ovarian and uterine clear cell carcinoma (CCC) and endometrioid carcinoma (EMCA). Loss-of-function mutations in ARID1A alter epigenetic regulation of transcription, cell-cycle checkpoint control, and DNA damage repair. We report here that mammalian cells with ARID1A deficiency harbor accumulated DNA base lesions and increased abasic (AP) sites, products of glycosylase in the first step of base excision repair (BER). ARID1A mutations also delayed recruitment kinetics of BER long-patch repair effectors. Although ARID1A-deficient tumors were not sensitive to monotherapy with DNA-methylating temozolomide (TMZ), the combination of TMZ with PARP inhibitors (PARPi) potently elicited double-strand DNA breaks, replication stress, and replication fork instability in ARID1A-deficient cells. The TMZ and PARPi combination also significantly delayed in vivo growth of ovarian tumor xenografts carrying ARID1A mutations and induced apoptosis and replication stress in xenograft tumors. Together, these findings identified a synthetic lethal strategy to enhance the response of ARID1A-mutated cancers to PARP inhibition, which warrants further experimental exploration and clinical trial validation.
SIGNIFICANCE
The combination of temozolomide and PARP inhibitor exploits the specific DNA damage repair status of ARID1A-inactivated ovarian cancers to suppress tumor growth.
Topics: Animals; Female; Humans; Poly(ADP-ribose) Polymerase Inhibitors; Temozolomide; Epigenesis, Genetic; Antineoplastic Agents; Ovarian Neoplasms; Mammals; DNA-Binding Proteins; Transcription Factors
PubMed: 37306706
DOI: 10.1158/0008-5472.CAN-22-3646 -
JAMA Oncology Aug 2023Acral melanoma, known for low tumor mutation burden, responds poorly to immunotherapy. A standard therapy is still lacking. (Randomized Controlled Trial)
Randomized Controlled Trial Clinical Trial
IMPORTANCE
Acral melanoma, known for low tumor mutation burden, responds poorly to immunotherapy. A standard therapy is still lacking.
OBJECTIVE
To investigate the activity and safety of camrelizumab (an anti-programmed cell death-1 antibody) plus apatinib (a vascular endothelial growth factor receptor 2 inhibitor) and temozolomide as first-line treatment in patients with advanced acral melanoma.
DESIGN, SETTING, AND PARTICIPANTS
In this single-arm, single-center, phase 2 nonrandomized clinical trial, patients with treatment-naive unresectable stage III or IV acral melanoma were enrolled at Peking University Cancer Hospital and Institute between June 4, 2020, and August 24, 2021. The data cutoff date was April 10, 2022.
INTERVENTIONS
Patients received 4-week cycles of intravenous camrelizumab, 200 mg, every 2 weeks; oral apatinib 250 mg, once daily; and intravenous temozolomide, 200 mg/m2, once daily on days 1 to 5 until disease progression or unacceptable toxic effects.
MAIN OUTCOMES AND MEASURES
The primary end point was objective response rate as assessed by investigators according to the Response Evaluation Criteria In Solid Tumors (version 1.1). Secondary end points included progression-free survival, time to response, duration of response, disease control rate, overall survival, and safety.
RESULTS
A total of 50 patients (32 men [64%]; median age, 57 years [IQR, 52-62 years]) were enrolled and received treatment. The median follow-up duration was 13.4 months (IQR, 9.6-16.2 months). The objective response rate was 64.0% (32 of 50; 95% CI, 49.2%-77.1%). The median time to response and duration of response were 2.7 months (IQR, 0.9-2.9 months) and 17.5 months (95% CI, 12.0 to not reached), respectively. The disease control rate was 88.0% (44 of 50; 95% CI, 75.7%-95.5%). The estimated median progression-free survival was 18.4 months (95% CI, 10.6 to not reached). The median overall survival was not reached. The most common grade 3 or 4 treatment-related adverse events were increased gamma-glutamyltransferase levels (15 [30%]), decreased neutrophil count (11 [22%]), increased conjugated bilirubin levels (10 [20%]), and increased aspartate aminotransferase levels (10 [20%]). No treatment-related deaths occurred.
CONCLUSIONS AND RELEVANCE
The findings of this nonrandomized clinical trial suggest that camrelizumab plus apatinib and temozolomide may be a potential first-line treatment option for patients with advanced acral melanoma, which warrants further validation in a randomized clinical trial.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT04397770.
Topics: Male; Humans; Middle Aged; Temozolomide; Vascular Endothelial Growth Factor A; Melanoma; Antineoplastic Combined Chemotherapy Protocols; Melanoma, Cutaneous Malignant
PubMed: 37261804
DOI: 10.1001/jamaoncol.2023.1363 -
Nature Communications Jul 2023Temozolomide (TMZ) therapy offers minimal clinical benefits in patients with glioblastoma multiforme (GBM) with high EGFR activity, underscoring the need for effective...
Temozolomide (TMZ) therapy offers minimal clinical benefits in patients with glioblastoma multiforme (GBM) with high EGFR activity, underscoring the need for effective combination therapy. Here, we show that tonicity-responsive enhancer binding protein (NFAT5) lysine methylation, is a determinant of TMZ response. Mechanistically, EGFR activation induces phosphorylated EZH2 (Ser21) binding and triggers NFAT5 methylation at K668. Methylation prevents NFAT5 cytoplasm interaction with E3 ligase TRAF6, thus blocks NFAT5 lysosomal degradation and cytosol localization restriction, which was mediated by TRAF6 induced K63-linked ubiquitination, resulting in NFAT5 protein stabilization, nuclear accumulation and activation. Methylated NFAT5 leads to the upregulation of MGMT, a transcriptional target of NFAT5, which is responsible for unfavorable TMZ response. Inhibition of NFAT5 K668 methylation improved TMZ efficacy in orthotopic xenografts and patient-derived xenografts (PDX) models. Notably, NFAT5 K668 methylation levels are elevated in TMZ-refractory specimens and confer poor prognosis. Our findings suggest targeting NFAT5 methylation is a promising therapeutic strategy to improve TMZ response in tumors with EGFR activation.
Topics: Humans; Glioblastoma; Temozolomide; Lysine; Methylation; TNF Receptor-Associated Factor 6; NFATC Transcription Factors; ErbB Receptors; Transcription Factors
PubMed: 37429858
DOI: 10.1038/s41467-023-39845-z -
Journal of Neuro-oncology Aug 2023Tumor Treating Fields (TTFields) therapy, an electric field-based cancer treatment, became FDA-approved for patients with newly diagnosed glioblastoma (GBM) in 2015... (Meta-Analysis)
Meta-Analysis Review
PURPOSE
Tumor Treating Fields (TTFields) therapy, an electric field-based cancer treatment, became FDA-approved for patients with newly diagnosed glioblastoma (GBM) in 2015 based on the randomized controlled EF-14 study. Subsequent approvals worldwide and increased adoption over time have raised the question of whether a consistent survival benefit has been observed in the real-world setting, and whether device usage has played a role.
METHODS
We conducted a literature search to identify clinical studies evaluating overall survival (OS) in TTFields-treated patients. Comparative and single-cohort studies were analyzed. Survival curves were pooled using a distribution-free random-effects method.
RESULTS
Among nine studies, seven (N = 1430 patients) compared the addition of TTFields therapy to standard of care (SOC) chemoradiotherapy versus SOC alone and were included in a pooled analysis for OS. Meta-analysis of comparative studies indicated a significant improvement in OS for patients receiving TTFields and SOC versus SOC alone (HR: 0.63; 95% CI 0.53-0.75; p < 0.001). Among real-world post-approval studies, the pooled median OS was 22.6 months (95% CI 17.6-41.2) for TTFields-treated patients, and 17.4 months (95% CI 14.4-21.6) for those not receiving TTFields. Rates of gross total resection were generally higher in the real-world setting, irrespective of TTFields use. Furthermore, for patients included in studies reporting data on device usage (N = 1015), an average usage rate of ≥ 75% was consistently associated with prolonged survival (p < 0.001).
CONCLUSIONS
Meta-analysis of comparative TTFields studies suggests survival may be improved with the addition of TTFields to SOC for patients with newly diagnosed GBM.
Topics: Humans; Glioblastoma; Temozolomide; Electric Stimulation Therapy; Brain Neoplasms; Combined Modality Therapy
PubMed: 37493865
DOI: 10.1007/s11060-023-04348-w -
Cancer Communications (London, England) Dec 2023Metabolism reprogramming plays a vital role in glioblastoma (GBM) progression and recurrence by producing enough energy for highly proliferating tumor cells. In...
BACKGROUND
Metabolism reprogramming plays a vital role in glioblastoma (GBM) progression and recurrence by producing enough energy for highly proliferating tumor cells. In addition, metabolic reprogramming is crucial for tumor growth and immune-escape mechanisms. Epidermal growth factor receptor (EGFR) amplification and EGFR-vIII mutation are often detected in GBM cells, contributing to the malignant behavior. This study aimed to investigate the functional role of the EGFR pathway on fatty acid metabolism remodeling and energy generation.
METHODS
Clinical GBM specimens were selected for single-cell RNA sequencing and untargeted metabolomics analysis. A metabolism-associated RTK-fatty acid-gene signature was constructed and verified. MK-2206 and MK-803 were utilized to block the RTK pathway and mevalonate pathway induced abnormal metabolism. Energy metabolism in GBM with activated EGFR pathway was monitored. The antitumor effect of Osimertinib and Atorvastatin assisted by temozolomide (TMZ) was analyzed by an intracranial tumor model in vivo.
RESULTS
GBM with high EGFR expression had characteristics of lipid remodeling and maintaining high cholesterol levels, supported by the single-cell RNA sequencing and metabolomics of clinical GBM samples. Inhibition of the EGFR/AKT and mevalonate pathways could remodel energy metabolism by repressing the tricarboxylic acid cycle and modulating ATP production. Mechanistically, the EGFR/AKT pathway upregulated the expressions of acyl-CoA synthetase short-chain family member 3 (ACSS3), acyl-CoA synthetase long-chain family member 3 (ACSL3), and long-chain fatty acid elongation-related gene ELOVL fatty acid elongase 2 (ELOVL2) in an NF-κB-dependent manner. Moreover, inhibition of the mevalonate pathway reduced the EGFR level on the cell membranes, thereby affecting the signal transduction of the EGFR/AKT pathway. Therefore, targeting the EGFR/AKT and mevalonate pathways enhanced the antitumor effect of TMZ in GBM cells and animal models.
CONCLUSIONS
Our findings not only uncovered the mechanism of metabolic reprogramming in EGFR-activated GBM but also provided a combinatorial therapeutic strategy for clinical GBM management.
Topics: Animals; Cell Line, Tumor; Energy Metabolism; ErbB Receptors; Fatty Acids; Glioblastoma; Ligases; Mevalonic Acid; Proto-Oncogene Proteins c-akt; Temozolomide
PubMed: 37920878
DOI: 10.1002/cac2.12502 -
Cancers May 2024The last 3 decades have witnessed a major evolution in the treatment of advanced-stage Hodgkin lymphoma (HL). The most prominent of these developments include the... (Review)
Review
The last 3 decades have witnessed a major evolution in the treatment of advanced-stage Hodgkin lymphoma (HL). The most prominent of these developments include the introduction of the international prognostic scoring (IPS) system; therapeutic decision-making based on both IPS and interim PET/CT data; the finding that a negative interim PET/CT result could be safely used for treatment de-escalation; the introduction of intensive combination chemotherapy like escalated BEACOPP (bleomycin, etoposide, adriamycin, cyclophosphamide, oncovin (vincristine), procarbazine, and prednisone); and further modification of this protocol with the incorporation of a conjugated anti-CD30 antibody brentuximab vedotin (BV) into first-line regimens, like BV-AVD (BV+ adriamycin, vinblastine and dacarbazine) and BrECADD (brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, and dexamethasone). The accruing data about the toxicity of the escalated BEACOPP protocol have led to decreasing the number of therapeutic cycles, substitution of toxic agents like procarbazine with dacarbazine (e.g., BEACOPDac), and reduction/omission of radiation therapy. Lately, a significant advancement has been made by the integration of checkpoint inhibitors in the first-line treatment, with preliminary results demonstrating the superiority of anti-PD1 combined with chemotherapy (nivolumab-AVD) compared to the BV-AVD regimen. This review aims to analyze recently published studies whose findings could change the treatment practice in advanced-stage HL.
PubMed: 38893177
DOI: 10.3390/cancers16112059 -
Neuro-oncology Jul 2023Efficient DNA repair in response to standard chemo and radiation therapies often contributes to glioblastoma (GBM) therapy resistance. Understanding the mechanisms of...
BACKGROUND
Efficient DNA repair in response to standard chemo and radiation therapies often contributes to glioblastoma (GBM) therapy resistance. Understanding the mechanisms of therapy resistance and identifying the drugs that enhance the therapeutic efficacy of standard therapies may extend the survival of GBM patients. In this study, we investigated the role of KDM1A/LSD1 in DNA double-strand break (DSB) repair and a combination of KDM1A inhibitor and temozolomide (TMZ) in vitro and in vivo using patient-derived glioma stem cells (GSCs).
METHODS
Brain bioavailability of the KDM1A inhibitor (NCD38) was established using LS-MS/MS. The effect of a combination of KDM1A knockdown or inhibition with TMZ was studied using cell viability and self-renewal assays. Mechanistic studies were conducted using CUT&Tag-seq, RNA-seq, RT-qPCR, western blot, homologous recombination (HR) and non-homologous end joining (NHEJ) reporter, immunofluorescence, and comet assays. Orthotopic murine models were used to study efficacy in vivo.
RESULTS
TCGA analysis showed KDM1A is highly expressed in TMZ-treated GBM patients. Knockdown or knockout or inhibition of KDM1A enhanced TMZ efficacy in reducing the viability and self-renewal of GSCs. Pharmacokinetic studies established that NCD38 readily crosses the blood-brain barrier. CUT&Tag-seq studies showed that KDM1A is enriched at the promoters of DNA repair genes and RNA-seq studies confirmed that KDM1A inhibition reduced their expression. Knockdown or inhibition of KDM1A attenuated HR and NHEJ-mediated DNA repair capacity and enhanced TMZ-mediated DNA damage. A combination of KDM1A knockdown or inhibition and TMZ treatment significantly enhanced the survival of tumor-bearing mice.
CONCLUSIONS
Our results provide evidence that KDM1A inhibition sensitizes GBM to TMZ via attenuation of DNA DSB repair pathways.
Topics: Animals; Mice; Temozolomide; Glioblastoma; Lysine; DNA Breaks, Double-Stranded; Tandem Mass Spectrometry; Cell Line, Tumor; Glioma; DNA Repair; DNA; Histone Demethylases; Drug Resistance, Neoplasm; Antineoplastic Agents, Alkylating; Brain Neoplasms; Xenograft Model Antitumor Assays
PubMed: 36652263
DOI: 10.1093/neuonc/noad018