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The New England Journal of Medicine Sep 2021Uveal melanoma is a disease that is distinct from cutaneous melanoma, with a low tumor mutational burden and a 1-year overall survival of approximately 50% in patients... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
Uveal melanoma is a disease that is distinct from cutaneous melanoma, with a low tumor mutational burden and a 1-year overall survival of approximately 50% in patients with metastatic uveal melanoma. Data showing a proven overall survival benefit with a systemic treatment are lacking. Tebentafusp is a bispecific protein consisting of an affinity-enhanced T-cell receptor fused to an anti-CD3 effector that can redirect T cells to target glycoprotein 100-positive cells.
METHODS
In this open-label, phase 3 trial, we randomly assigned previously untreated HLA-A*02:01-positive patients with metastatic uveal melanoma in a 2:1 ratio to receive tebentafusp (tebentafusp group) or the investigator's choice of therapy with single-agent pembrolizumab, ipilimumab, or dacarbazine (control group), stratified according to the lactate dehydrogenase level. The primary end point was overall survival.
RESULTS
A total of 378 patients were randomly assigned to either the tebentafusp group (252 patients) or the control group (126 patients). Overall survival at 1 year was 73% in the tebentafusp group and 59% in the control group (hazard ratio for death, 0.51; 95% confidence interval [CI], 0.37 to 0.71; P<0.001) in the intention-to-treat population. Progression-free survival was also significantly higher in the tebentafusp group than in the control group (31% vs. 19% at 6 months; hazard ratio for disease progression or death, 0.73; 95% CI, 0.58 to 0.94; P = 0.01). The most common treatment-related adverse events in the tebentafusp group were cytokine-mediated events (due to T-cell activation) and skin-related events (due to glycoprotein 100-positive melanocytes), including rash (83%), pyrexia (76%), and pruritus (69%). These adverse events decreased in incidence and severity after the first three or four doses and infrequently led to discontinuation of the trial treatment (2%). No treatment-related deaths were reported.
CONCLUSIONS
Treatment with tebentafusp resulted in longer overall survival than the control therapy among previously untreated patients with metastatic uveal melanoma. (Funded by Immunocore; ClinicalTrials.gov number, NCT03070392; EudraCT number, 2015-003153-18.).
Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Cytokine Release Syndrome; Dacarbazine; Exanthema; Female; Humans; Ipilimumab; Male; Melanoma; Middle Aged; Recombinant Fusion Proteins; Survival Analysis; Uveal Neoplasms
PubMed: 34551229
DOI: 10.1056/NEJMoa2103485 -
International Journal of Molecular... Jun 2022(1) Background: Glioblastoma is the most frequent and lethal primary tumor of the central nervous system. Through many years, research has brought various advances in... (Review)
Review
(1) Background: Glioblastoma is the most frequent and lethal primary tumor of the central nervous system. Through many years, research has brought various advances in glioblastoma treatment. At this time, glioblastoma management is based on maximal safe surgical resection, radiotherapy, and chemotherapy with temozolomide. Recently, bevacizumab has been added to the treatment arsenal for the recurrent scenario. Nevertheless, patients with glioblastoma still have a poor prognosis. Therefore, many efforts are being made in different clinical research areas to find a new alternative to improve overall survival, free-progression survival, and life quality in glioblastoma patients. (2) Methods: Our objective is to recap the actual state-of-the-art in glioblastoma treatment, resume the actual research and future perspectives on immunotherapy, as well as the new synthetic molecules and natural compounds that represent potential future therapies at preclinical stages. (3) Conclusions: Despite the great efforts in therapeutic research, glioblastoma management has suffered minimal changes, and the prognosis remains poor. Combined therapeutic strategies and delivery methods, including immunotherapy, synthetic molecules, natural compounds, and glioblastoma stem cell inhibition, may potentiate the standard of care therapy and represent the next step in glioblastoma management research.
Topics: Bevacizumab; Brain Neoplasms; Dacarbazine; Glioblastoma; Humans; Temozolomide
PubMed: 35806212
DOI: 10.3390/ijms23137207 -
Journal of Clinical Oncology : Official... Jan 2023The prognosis of patients with early-stage unfavorable Hodgkin lymphoma remains unsatisfactory. We assessed the efficacy and safety of brentuximab vedotin plus... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
The prognosis of patients with early-stage unfavorable Hodgkin lymphoma remains unsatisfactory. We assessed the efficacy and safety of brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (BV-AVD) in previously untreated, early-stage unfavorable Hodgkin lymphoma (ClinicalTrials.gov identifier: NCT02292979).
METHODS
BREACH is a multicenter, randomized, open-label, phase II trial. Eligible patients were age 18-60 years with ≥ 1 unfavorable EORTC/LYSA criterion. Patients were randomly assigned (2:1) to four cycles of BV-AVD or standard doxorubicin, bleomycin, vincristine, and dacarbazine (ABVD), followed by 30 Gy involved node radiotherapy. The primary end point was the positron emission tomography (PET) response rate after two cycles by expert independent review using the Deauville score. The study was designed to test if the PET-negative rate after two cycles of BV-AVD was superior to 75%. We hypothesized a 10% increase in the PET-negative rate after two cycles of BV-AVD.
RESULTS
Between March 2015 and October 2016, 170 patients were enrolled. After two cycles, the primary end point of the study was met: 93 (82.3%; 90% CI, 75.3 to 88.0) of 113 patients in the BV-AVD arm were PET-negative (Deauville score 1-3) compared with 43 (75.4%; 90% CI, 64.3% to 84.5%) of 57 in the ABVD arm. The 2-year progression-free survival (PFS) was 97.3% (95% CI, 91.9 to 99.1) and 92.6% (95% CI, 81.4% to 97.2%) in the BV-AVD and ABVD arms, respectively. High total metabolic tumor volume was associated with a significantly shorter PFS (hazard ratio, 17.9; 95% CI, 2.2 to 145.5; < .001). For patients with high total metabolic tumor volume, the 2-year PFS rate was 90.9% (95% CI, 74.4 to 97.0) and 70.7% (95% CI, 39.4% to 87.9%) in the BV-AVD and ABVD arms, respectively.
CONCLUSION
BV-AVD demonstrated an improvement in the PET-negative rate compared with ABVD after two cycles.
Topics: Humans; Adolescent; Young Adult; Adult; Middle Aged; Hodgkin Disease; Brentuximab Vedotin; Bleomycin; Vinblastine; Doxorubicin; Antineoplastic Combined Chemotherapy Protocols; Dacarbazine; Neoplasm Staging; Treatment Outcome
PubMed: 35867960
DOI: 10.1200/JCO.21.01281 -
Journal of Clinical Oncology : Official... Mar 2023Patients with advanced pancreatic neuroendocrine tumors (NETs) have few treatment options that yield objective responses. Retrospective and small prospective studies... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Patients with advanced pancreatic neuroendocrine tumors (NETs) have few treatment options that yield objective responses. Retrospective and small prospective studies suggest that capecitabine and temozolomide are associated with high response rates (RRs) and long progression-free survival (PFS).
PATIENTS AND METHODS
E2211 was a multicenter, randomized, phase II trial comparing temozolomide versus capecitabine/temozolomide in patients with advanced low-grade or intermediate-grade pancreatic NETs. Key eligibility criteria included progression within the preceding 12 months and no prior temozolomide, dimethyl-triazeno-imidazole-carboxamide or dacarbazine, capecitabine or fluorouracil. The primary end point was PFS; secondary endpoints were overall survival, RR, safety, and methylguanine methyltransferase (MGMT) by immunohistochemistry and promoter methylation.
RESULTS
A total of 144 patients were enrolled between April 2013 and March 2016 to temozolomide (n = 72) or capecitabine and temozolomide (n = 72); the primary analysis population included 133 eligible patients. At the scheduled interim analysis in January 2018, the median PFS was 14.4 months for temozolomide versus 22.7 months for capecitabine/temozolomide (hazard ratio = 0.58), which was sufficient to reject the null hypothesis for the primary end point (stratified log-rank = .022). In the final analysis (May 2021), the median overall survival was 53.8 months for temozolomide and 58.7 months for capecitabine/temozolomide (hazard ratio = 0.82, = .42). MGMT deficiency was associated with response.
CONCLUSION
The combination of capecitabine/temozolomide was associated with a significant improvement in PFS compared with temozolomide alone in patients with advanced pancreatic NETs. The median PFS and RR observed with capecitabine/temozolomide are the highest reported in a randomized study for pancreatic NETs. MGMT deficiency was associated with response, and although routine MGMT testing is not recommended, it can be considered for select patients in need of objective response (ClinicalTrials.gov identifier: NCT01824875).
Topics: Humans; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Dacarbazine; Neuroendocrine Tumors; Pancreatic Neoplasms; Prospective Studies; Retrospective Studies; Temozolomide; Treatment Outcome
PubMed: 36260828
DOI: 10.1200/JCO.22.01013 -
The Lancet. Oncology Jun 2021The CATNON trial investigated the addition of concurrent, adjuvant, and both current and adjuvant temozolomide to radiotherapy in adults with newly diagnosed 1p/19q... (Randomized Controlled Trial)
Randomized Controlled Trial
Adjuvant and concurrent temozolomide for 1p/19q non-co-deleted anaplastic glioma (CATNON; EORTC study 26053-22054): second interim analysis of a randomised, open-label, phase 3 study.
BACKGROUND
The CATNON trial investigated the addition of concurrent, adjuvant, and both current and adjuvant temozolomide to radiotherapy in adults with newly diagnosed 1p/19q non-co-deleted anaplastic gliomas. The benefit of concurrent temozolomide chemotherapy and relevance of mutations in the IDH1 and IDH2 genes remain unclear.
METHODS
This randomised, open-label, phase 3 study done in 137 institutions across Australia, Europe, and North America included patients aged 18 years or older with newly diagnosed 1p/19q non-co-deleted anaplastic gliomas and a WHO performance status of 0-2. Patients were randomly assigned (1:1:1:1) centrally using a minimisation technique to radiotherapy alone (59·4 Gy in 33 fractions; three-dimensional conformal radiotherapy or intensity-modulated radiotherapy), radiotherapy with concurrent oral temozolomide (75 mg/m per day), radiotherapy with adjuvant oral temozolomide (12 4-week cycles of 150-200 mg/m temozolomide given on days 1-5), or radiotherapy with both concurrent and adjuvant temozolomide. Patients were stratified by institution, WHO performance status score, age, 1p loss of heterozygosity, the presence of oligodendroglial elements on microscopy, and MGMT promoter methylation status. The primary endpoint was overall survival adjusted by stratification factors at randomisation in the intention-to-treat population. A second interim analysis requested by the independent data monitoring committee was planned when two-thirds of total required events were observed to test superiority or futility of concurrent temozolomide. This study is registered with ClinicalTrials.gov, NCT00626990.
FINDINGS
Between Dec 4, 2007, and Sept 11, 2015, 751 patients were randomly assigned (189 to radiotherapy alone, 188 to radiotherapy with concurrent temozolomide, 186 to radiotherapy and adjuvant temozolomide, and 188 to radiotherapy with concurrent and adjuvant temozolomide). Median follow-up was 55·7 months (IQR 41·0-77·3). The second interim analysis declared futility of concurrent temozolomide (median overall survival was 66·9 months [95% CI 45·7-82·3] with concurrent temozolomide vs 60·4 months [45·7-71·5] without concurrent temozolomide; hazard ratio [HR] 0·97 [99·1% CI 0·73-1·28], p=0·76). By contrast, adjuvant temozolomide improved overall survival compared with no adjuvant temozolomide (median overall survival 82·3 months [95% CI 67·2-116·6] vs 46·9 months [37·9-56·9]; HR 0·64 [95% CI 0·52-0·79], p<0·0001). The most frequent grade 3 and 4 toxicities were haematological, occurring in no patients in the radiotherapy only group, 16 (9%) of 185 patients in the concurrent temozolomide group, and 55 (15%) of 368 patients in both groups with adjuvant temozolomide. No treatment-related deaths were reported.
INTERPRETATION
Adjuvant temozolomide chemotherapy, but not concurrent temozolomide chemotherapy, was associated with a survival benefit in patients with 1p/19q non-co-deleted anaplastic glioma. Clinical benefit was dependent on IDH1 and IDH2 mutational status.
FUNDING
Merck Sharpe & Dohme.
Topics: Adolescent; Adult; Aged; Australia; Chemotherapy, Adjuvant; Chromosomes, Human, Pair 1; Chromosomes, Human, Pair 19; Combined Modality Therapy; Dacarbazine; Europe; Female; Glioma; Humans; Isocitrate Dehydrogenase; Loss of Heterozygosity; Male; Middle Aged; North America; Radiotherapy, Conformal; Temozolomide; Young Adult
PubMed: 34000245
DOI: 10.1016/S1470-2045(21)00090-5 -
Science (New York, N.Y.) Jul 2022Approximately half of glioblastoma and more than two-thirds of grade II and III glioma tumors lack the DNA repair protein O-methylguanine methyl transferase (MGMT)....
Approximately half of glioblastoma and more than two-thirds of grade II and III glioma tumors lack the DNA repair protein O-methylguanine methyl transferase (MGMT). MGMT-deficient tumors respond initially to the DNA methylation agent temozolomide (TMZ) but frequently acquire resistance through loss of the mismatch repair (MMR) pathway. We report the development of agents that overcome this resistance mechanism by inducing MMR-independent cell killing selectively in MGMT-silenced tumors. These agents deposit a dynamic DNA lesion that can be reversed by MGMT but slowly evolves into an interstrand cross-link in MGMT-deficient settings, resulting in MMR-independent cell death with low toxicity in vitro and in vivo. This discovery may lead to new treatments for gliomas and may represent a new paradigm for designing chemotherapeutics that exploit specific DNA repair defects.
Topics: Antineoplastic Agents, Alkylating; Brain Neoplasms; Cell Line, Tumor; DNA Methylation; DNA Modification Methylases; DNA Repair; DNA Repair Enzymes; Dacarbazine; Drug Design; Drug Resistance, Neoplasm; Glioblastoma; Humans; Temozolomide; Tumor Suppressor Proteins
PubMed: 35901163
DOI: 10.1126/science.abn7570 -
Cell Research Oct 2021Glioblastoma (GBM) is a prevalent and highly lethal form of glioma, with rapid tumor progression and frequent recurrence. Excessive outgrowth of pericytes in GBM governs...
Glioblastoma (GBM) is a prevalent and highly lethal form of glioma, with rapid tumor progression and frequent recurrence. Excessive outgrowth of pericytes in GBM governs the ecology of the perivascular niche, but their function in mediating chemoresistance has not been fully explored. Herein, we uncovered that pericytes potentiate DNA damage repair (DDR) in GBM cells residing in the perivascular niche, which induces temozolomide (TMZ) chemoresistance. We found that increased pericyte proportion correlates with accelerated tumor recurrence and worse prognosis. Genetic depletion of pericytes in GBM xenografts enhances TMZ-induced cytotoxicity and prolongs survival of tumor-bearing mice. Mechanistically, C-C motif chemokine ligand 5 (CCL5) secreted by pericytes activates C-C motif chemokine receptor 5 (CCR5) on GBM cells to enable DNA-dependent protein kinase catalytic subunit (DNA-PKcs)-mediated DDR upon TMZ treatment. Disrupting CCL5-CCR5 paracrine signaling through the brain-penetrable CCR5 antagonist maraviroc (MVC) potently inhibits pericyte-promoted DDR and effectively improves the chemotherapeutic efficacy of TMZ. GBM patient-derived xenografts with high CCL5 expression benefit from combined treatment with TMZ and MVC. Our study reveals the role of pericytes as an extrinsic stimulator potentiating DDR signaling in GBM cells and suggests that targeting CCL5-CCR5 signaling could be an effective therapeutic strategy to improve chemotherapeutic efficacy against GBM.
Topics: Animals; Cell Line, Tumor; Drug Resistance, Neoplasm; Glioblastoma; Mice; Paracrine Communication; Pericytes; Temozolomide; Xenograft Model Antitumor Assays
PubMed: 34239070
DOI: 10.1038/s41422-021-00528-3 -
Clinical Cancer Research : An Official... May 2022To investigate the antitumor activity of a mitochondrial-localized HSP90 inhibitor, Gamitrinib, in multiple glioma models, and to elucidate the antitumor mechanisms of...
PURPOSE
To investigate the antitumor activity of a mitochondrial-localized HSP90 inhibitor, Gamitrinib, in multiple glioma models, and to elucidate the antitumor mechanisms of Gamitrinib in gliomas.
EXPERIMENTAL DESIGN
A broad panel of primary and temozolomide (TMZ)-resistant human glioma cell lines were screened by cell viability assays, flow cytometry, and crystal violet assays to investigate the therapeutic efficacy of Gamitrinib. Seahorse assays were used to measure the mitochondrial respiration of glioma cells. Integrated analyses of RNA sequencing (RNAseq) and reverse phase protein array (RPPA) data were performed to reveal the potential antitumor mechanisms of Gamitrinib. Neurospheres, patient-derived organoids (PDO), cell line-derived xenografts (CDX), and patient-derived xenografts (PDX) models were generated to further evaluate the therapeutic efficacy of Gamitrinib.
RESULTS
Gamitrinib inhibited cell proliferation and induced cell apoptosis and death in 17 primary glioma cell lines, 6 TMZ-resistant glioma cell lines, 4 neurospheres, and 3 PDOs. Importantly, Gamitrinib significantly delayed the tumor growth and improved survival of mice in both CDX and PDX models in which tumors were either subcutaneously or intracranially implanted. Integrated computational analyses of RNAseq and RPPA data revealed that Gamitrinib exhibited its antitumor activity via (i) suppressing mitochondrial biogenesis, OXPHOS, and cell-cycle progression and (ii) activating the energy-sensing AMP-activated kinase, DNA damage, and stress response.
CONCLUSIONS
These preclinical findings established the therapeutic role of Gamitrinib in gliomas and revealed the inhibition of mitochondrial biogenesis and tumor bioenergetics as the primary antitumor mechanisms in gliomas.
Topics: Animals; Antineoplastic Agents; Brain Neoplasms; Cell Line, Tumor; Glioma; Humans; Mice; Mitochondria; Temozolomide; Xenograft Model Antitumor Assays
PubMed: 35247901
DOI: 10.1158/1078-0432.CCR-21-0833 -
Cancer Jun 2020The optimal treatment for advanced leiomyosarcoma is still debated. Given histotype-specific prospective controlled data lacking, this study retrospectively evaluated...
Doxorubicin plus dacarbazine, doxorubicin plus ifosfamide, or doxorubicin alone as a first-line treatment for advanced leiomyosarcoma: A propensity score matching analysis from the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group.
BACKGROUND
The optimal treatment for advanced leiomyosarcoma is still debated. Given histotype-specific prospective controlled data lacking, this study retrospectively evaluated doxorubicin plus dacarbazine, doxorubicin plus ifosfamide, and doxorubicin alone as first-line treatments for advanced/metastatic leiomyosarcoma treated at European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group (EORTC-STBSG) sites.
METHODS
The inclusion criteria were a confirmed histological diagnosis, treatment between January 2010 and December 2015, measurable disease (Response Evaluation Criteria in Solid Tumors 1.1), an Eastern Cooperative Oncology Group performance status ≤2, and an age ≥ 18 years. The endpoints were progression-free survival (PFS), overall survival (OS), and overall response rate (ORR). PFS was analyzed with methods for interval-censored data. Patients were matched according to their propensity scores, which were estimated with a logistic regression model accounting for histology, grade, age, sex, performance status, tumor site, and tumor extent.
RESULTS
Three hundred three patients from 18 EORTC-STBSG sites were identified. One hundred seventeen (39%) received doxorubicin plus dacarbazine, 71 (23%) received doxorubicin plus ifosfamide, and 115 (38%) received doxorubicin. In the 2:1:2 propensity score-matched population (205 patients), the estimated median PFS was 9.2 months (95% confidence interval [CI], 5.2-9.7 months), 8.2 months (95% CI, 5.2-10.1 months), and 4.8 months (95% CI, 2.3-6.0 months) with ORRs of 30.9%, 19.5%, and 25.6% for doxorubicin plus dacarbazine, doxorubicin plus ifosfamide, and doxorubicin alone, respectively. PFS was significantly longer with doxorubicin plus dacarbazine versus doxorubicin (hazard ratio [HR], 0.72; 95% CI, 0.52-0.99). Doxorubicin plus dacarbazine was associated with longer OS (median, 36.8 months; 95% CI, 27.9-47.2 months) in comparison with both doxorubicin plus ifosfamide (median, 21.9 months; 95% CI, 16.7-33.4 months; HR, 0.65; 95% CI, 0.40-1.06) and doxorubicin (median, 30.3 months; 95% CI, 21.0-36.3 months; HR, 0.66; 95% CI, 0.43-0.99). Adjusted analyses retained an effect for PFS but not for OS. None of the factors selected for multivariate analysis had a significant interaction with the received treatment for both PFS and OS.
CONCLUSIONS
This is the largest retrospective study of first-line treatment for advanced leiomyosarcoma. In the propensity score-matched population, doxorubicin and dacarbazine showed favorable activity in terms of both ORR and PFS and warrants further evaluation in prospective trials.
Topics: Adult; Aged; Aged, 80 and over; Bone Neoplasms; Dacarbazine; Doxorubicin; Female; Humans; Ifosfamide; Leiomyosarcoma; Male; Middle Aged; Propensity Score; Retrospective Studies; Sarcoma
PubMed: 32129883
DOI: 10.1002/cncr.32795 -
Theranostics 2022The concentration and duration of intracellular drugs have always been the key factors for determining the efficacy of the treatment. Efflux of chemotherapeutic drugs...
The concentration and duration of intracellular drugs have always been the key factors for determining the efficacy of the treatment. Efflux of chemotherapeutic drugs or anticancer agents is a major reason for multidrug resistance generation in cancer cells. The high expression of polymerase I and transcript release factor (PTRF) is correlated with a worse prognosis in glioma patients. However, the importance of PTRF on temozolomide (TMZ) resistance in glioblastoma (GBM) is poorly understood. TCGA data analysis, CGGA data analysis, transmission electron microscopy (TEM), scanning electron microscopy (SEM), clone formation, cell counting kit-8 (cck-8), western blot (WB), immunofluorescence (IF), immunohistochemistry (IHC) and flow cytometry assays were performed to investigate the underlying mechanism and effect of PTRF on TMZ-resistance in a variety of GBM cell lines and GBM patient-derived xenograft (PDX) models. Clone formation, WB, IF, IHC and flow cytometry assays were performed to examine the efficacy of sequential therapy of TMZ followed by CQ in GBM cells and PDX models. The prognosis of GBM patients treated with TMZ was negatively correlated with PTRF expression. Our results reveal that PTRF knockdown significantly decrease proliferation and increase apoptosis in GBM after TMZ treatment. Moreover, PTRF contribute to TMZ-resistance by increasing TMZ efflux through extracellular vesicles (EVs). Furthermore, our results demonstrate that sequential therapy of TMZ followed by CQ significantly promotes the TMZ efficacy against GBM by increasing intracellular TMZ concentration ([TMZ]i). This study highlights that PTRF can act as an independent biomarker to predict the prognosis of GBM patients after TMZ treatment and describes a new mechanism contributing to TMZ-resistance. In addition, this study may provide a novel idea for GBM therapy.
Topics: Antineoplastic Agents, Alkylating; Brain Neoplasms; Cell Line, Tumor; Drug Resistance, Neoplasm; Extracellular Vesicles; Glioblastoma; Humans; Temozolomide; Xenograft Model Antitumor Assays
PubMed: 35673568
DOI: 10.7150/thno.71763