This document summarizes the results of a randomized, double-blind clinical trial that evaluated the efficacy and safety of adding the monoclonal antibody nimotuzumab to radiotherapy for the treatment of high-grade glioma patients. 70 patients received either nimotuzumab plus radiotherapy or a placebo plus radiotherapy. The combination of nimotuzumab and radiotherapy was well-tolerated with the most common side effects being nausea, fever, tremors, anorexia and liver test abnormalities. Median survival was significantly longer in the nimotuzumab group compared to the placebo group (17.76 months vs 12.63 months). Nimotuzumab showed a good safety profile and provided a survival benefit when added to radi
Newer biomarkers,techniques & their inclusion in 2016 WHO classification for leukaemia/lymphomas increases the responsibility of the pathologists, requiring to develop an integrated multidisciplinary approach for reporting.
This slidedeck presents an up-to-date disease overview of BCC, reviews current treatment options in BCC, explains the hedgehog signaling pathway and its role in BCC, review recent data of the first-in-class hedgehog inhibitor, vismodegib, and other novel agents in clinical trials. Faculty will also review recently approved novel agents in melanoma, to include treatment planning and managing adverse events. Case studies will demonstrate the practical application of current and emerging clinical evidence for the treatment of BCC and melanoma. During the panel discussion, faculty will discuss the importance of cross-communication in the treatment planning process and strategies to optimize the continuum of care for patients with BCC.
Dr. Ignacio Melero - Simposio Internacional 'Terapias oncológicas avanzadas''Fundación Ramón Areces
Los días 15 y 16 de octubre de 2014, la Fundación Ramón Areces y la Real Academia Nacional de Farmacia, en colaboración con la Fundación de la Innovación Bankinter, reunieron en Madrid a algunos de los mayores expertos mundiales en nuevas terapias contra el cáncer. El Simposio Internacional, coordinado por la profesora y académica María José Alonso, analizó el momento actual de la lucha contra esta enfermedad. También fue un punto de encuentro para científicos de los más innovadores institutos de investigación en oncología, quienes debatieron sobre tres grandes temas: la Medicina Personalizada contra el cáncer, los nanomedicamentos en la terapia del cáncer y las terapias basadas en la inmunomodulación.
This document discusses chemotherapy for central nervous system (CNS) tumors. It covers the history of chemotherapy for CNS malignancies and CNS-active drugs. Some key challenges in CNS chemotherapy include the blood-brain barrier, blood-CSF barrier, drug efflux transporters, and spatial distribution of tumor cells. Strategies to increase drug delivery to brain tumors include liposomal drugs, high-dose chemotherapy, selective intra-arterial infusion, inhibiting drug efflux, and direct administration into the CNS. Common chemotherapy regimens discussed for CNS tumors include temozolomide with radiation for glioblastoma, PCV for oligodendroglioma and medulloblastoma, and targeted therapies for
This document summarizes various cancer immunotherapies including immune checkpoint inhibitors like anti-CTLA-4 and anti-PD-1 antibodies. It discusses clinical trials of these therapies in treating cancers like melanoma, non-small cell lung cancer, and renal cancer. The trials showed improved overall survival, progression-free survival, and response rates compared to chemotherapy or standard treatments. Adverse events were manageable and responses did not depend on dose or PD-L1 expression levels. Biomarkers to predict response are still being investigated.
Cetuximab treatment in a patient with metastatic colorectaleman youssif
This case report describes a patient with metastatic colorectal cancer and lifelong psoriasis who was treated with cetuximab monoclonal antibody. During treatment with cetuximab, the patient experienced improvement of both his cancer and psoriasis. His liver metastases nearly completely regressed and his psoriasis lesions considerably reduced in intensity. The report concludes that cetuximab may be safely offered to colorectal cancer patients with psoriasis, as it can induce remission of both cancer and psoriasis by regulating abnormal epidermal growth factor receptor metabolism in the skin.
This meta-analysis examined whether carmustine wafer treatment could improve survival rates in patients with newly diagnosed glioblastoma multiforme (GBM). Six studies with a total of 513 patients were analyzed. The results showed that carmustine wafers reduced the risk of death by 37% in newly diagnosed GBM patients. When pooling all studies, there was a significant survival advantage for patients receiving carmustine wafers. However, the two randomized controlled trials did not individually show a significant survival benefit. The analysis concluded that carmustine-impregnated wafers can improve survival in newly diagnosed GBM patients when used as an adjunct to surgery and radiation therapy.
Newer management techniques for glioblastomaabhitux
Local therapies for brain tumors involve directly administering therapeutic agents into or near the tumor to produce an anti-tumor effect. Gliadel wafers, which slowly release the chemotherapy drug BCNU, have been shown in clinical trials to improve survival outcomes for patients with malignant glioma when implanted during surgery compared to placebo wafers. While Gliadel can cause side effects like edema and healing abnormalities, its benefits outweigh the risks. Convection-enhanced delivery is a method for directly infusing drugs into brain tumors that may help overcome issues like poor drug penetration and resistance.
Newer biomarkers,techniques & their inclusion in 2016 WHO classification for leukaemia/lymphomas increases the responsibility of the pathologists, requiring to develop an integrated multidisciplinary approach for reporting.
This slidedeck presents an up-to-date disease overview of BCC, reviews current treatment options in BCC, explains the hedgehog signaling pathway and its role in BCC, review recent data of the first-in-class hedgehog inhibitor, vismodegib, and other novel agents in clinical trials. Faculty will also review recently approved novel agents in melanoma, to include treatment planning and managing adverse events. Case studies will demonstrate the practical application of current and emerging clinical evidence for the treatment of BCC and melanoma. During the panel discussion, faculty will discuss the importance of cross-communication in the treatment planning process and strategies to optimize the continuum of care for patients with BCC.
Dr. Ignacio Melero - Simposio Internacional 'Terapias oncológicas avanzadas''Fundación Ramón Areces
Los días 15 y 16 de octubre de 2014, la Fundación Ramón Areces y la Real Academia Nacional de Farmacia, en colaboración con la Fundación de la Innovación Bankinter, reunieron en Madrid a algunos de los mayores expertos mundiales en nuevas terapias contra el cáncer. El Simposio Internacional, coordinado por la profesora y académica María José Alonso, analizó el momento actual de la lucha contra esta enfermedad. También fue un punto de encuentro para científicos de los más innovadores institutos de investigación en oncología, quienes debatieron sobre tres grandes temas: la Medicina Personalizada contra el cáncer, los nanomedicamentos en la terapia del cáncer y las terapias basadas en la inmunomodulación.
This document discusses chemotherapy for central nervous system (CNS) tumors. It covers the history of chemotherapy for CNS malignancies and CNS-active drugs. Some key challenges in CNS chemotherapy include the blood-brain barrier, blood-CSF barrier, drug efflux transporters, and spatial distribution of tumor cells. Strategies to increase drug delivery to brain tumors include liposomal drugs, high-dose chemotherapy, selective intra-arterial infusion, inhibiting drug efflux, and direct administration into the CNS. Common chemotherapy regimens discussed for CNS tumors include temozolomide with radiation for glioblastoma, PCV for oligodendroglioma and medulloblastoma, and targeted therapies for
This document summarizes various cancer immunotherapies including immune checkpoint inhibitors like anti-CTLA-4 and anti-PD-1 antibodies. It discusses clinical trials of these therapies in treating cancers like melanoma, non-small cell lung cancer, and renal cancer. The trials showed improved overall survival, progression-free survival, and response rates compared to chemotherapy or standard treatments. Adverse events were manageable and responses did not depend on dose or PD-L1 expression levels. Biomarkers to predict response are still being investigated.
Cetuximab treatment in a patient with metastatic colorectaleman youssif
This case report describes a patient with metastatic colorectal cancer and lifelong psoriasis who was treated with cetuximab monoclonal antibody. During treatment with cetuximab, the patient experienced improvement of both his cancer and psoriasis. His liver metastases nearly completely regressed and his psoriasis lesions considerably reduced in intensity. The report concludes that cetuximab may be safely offered to colorectal cancer patients with psoriasis, as it can induce remission of both cancer and psoriasis by regulating abnormal epidermal growth factor receptor metabolism in the skin.
This meta-analysis examined whether carmustine wafer treatment could improve survival rates in patients with newly diagnosed glioblastoma multiforme (GBM). Six studies with a total of 513 patients were analyzed. The results showed that carmustine wafers reduced the risk of death by 37% in newly diagnosed GBM patients. When pooling all studies, there was a significant survival advantage for patients receiving carmustine wafers. However, the two randomized controlled trials did not individually show a significant survival benefit. The analysis concluded that carmustine-impregnated wafers can improve survival in newly diagnosed GBM patients when used as an adjunct to surgery and radiation therapy.
Newer management techniques for glioblastomaabhitux
Local therapies for brain tumors involve directly administering therapeutic agents into or near the tumor to produce an anti-tumor effect. Gliadel wafers, which slowly release the chemotherapy drug BCNU, have been shown in clinical trials to improve survival outcomes for patients with malignant glioma when implanted during surgery compared to placebo wafers. While Gliadel can cause side effects like edema and healing abnormalities, its benefits outweigh the risks. Convection-enhanced delivery is a method for directly infusing drugs into brain tumors that may help overcome issues like poor drug penetration and resistance.
Chemotherapy is an important treatment option for both primary and secondary brain tumours. For primary brain tumours, temozolomide is often used in combination with radiation therapy for glioblastoma based on results from the landmark Stupp trial showing improved survival. Other drugs commonly used include carmustine, PCV regimen, platinum agents and targeted therapies such as bevacizumab are being investigated. Ongoing clinical trials are evaluating these agents in various settings and combinations to improve outcomes for brain cancer patients.
Dr. Patrick Hwu presents the latest information on immunotherapies for melanoma at the MRF's Patient Symposium at MD Anderson Cancer Center on January 31, 2015.
(1) The document summarizes the PORTEC 4A trial, which aims to evaluate molecular risk profiling to guide adjuvant treatment decisions in early-stage endometrial cancer.
(2) The trial compares adjuvant vaginal brachytherapy, the current standard, to a molecular profiling-based approach that may recommend observation, brachytherapy, or pelvic radiation.
(3) Based on previous studies, it is estimated that 50-55% of patients will be low risk and need only observation, 40% intermediate risk requiring brachytherapy, and 5-10% high risk needing pelvic radiation. The goal is to reduce overtreatment while maintaining local control.
Role of molecular targeted therapy in HCC DubaiPAIRS WEB
This document discusses hepatocellular carcinoma (HCC) and approaches to treating this growing clinical challenge. It provides background on HCC pathogenesis and prognostic factors such as tumor stage, liver function, and tumor biology. Treatment options including curative therapies for early stage disease and palliative options for advanced HCC are described. The role of the targeted therapy sorafenib in treating advanced HCC is summarized based on results from Phase III trials showing it can prolong both overall survival and time to progression compared to placebo. Ongoing research into additional targeted agents and combination approaches for HCC are also mentioned.
This document summarizes key findings from several studies related to acute myeloid leukemia (AML) in elderly patients:
1) A phase 3 trial found that azacitidine extended overall survival compared to conventional care regimens in older patients with newly diagnosed AML, with median OS of 10.4 months for azacitidine vs 6.5 months for conventional care.
2) Subanalyses found azacitidine provided particularly long OS benefits vs conventional care for patients with poor-risk cytogenetics (median OS 6.4 vs 3.2 months) or myelodysplasia-related changes (1-year OS 55.1% vs 31.3% for LDAC preselected
Diagnosing PM/DM is challenging due to rarity of the disease, their similar clinical presentation and the possibility of overlap syndromes. A comprehensive strategy for serological testing comprises of parallel determination of both MSA and MAA thereby reducing the time to diagnosis. Current immunoassays techniques (Immunoblot) targeting MAA & MSAs have –
The ability to include many parameters simultaneously which ensures higher detection rate; Become readily accessible & hence an opportunity for laboratories to contribute significantly in the disease diagnosis. MSA are highly specific for PM/DM, and many of them are also associated with a unique clinical subset of PM/DM, making them useful clinical diagnostic/prognostic biomarkers & continue to evolve.
This document summarizes the results of a clinical trial investigating the efficacy and safety of pembrolizumab (anti-PD-1 antibody) in patients with advanced melanoma that progressed after treatment with ipilimumab. The overall response rate was 26% in the 2 mg/kg group and 10% in the 10 mg/kg group, with responses ongoing after 1 year. Pembrolizumab demonstrated a manageable safety profile, with grade 3-4 drug-related adverse events occurring in 12% of patients. This trial provides evidence that pembrolizumab is an effective treatment option for patients with advanced melanoma who have progressed on ipilimumab.
1) High grade gliomas include grade III anaplastic astrocytomas, anaplastic oligodendrogliomas, and grade IV glioblastomas.
2) The standard of care for glioblastoma is maximal safe surgical resection followed by radiotherapy with concurrent and adjuvant temozolomide chemotherapy. Molecular markers like MGMT promoter methylation and IDH1 mutation provide prognostic information.
3) For anaplastic gliomas, the treatment involves surgical resection followed by radiotherapy. For anaplastic gliomas with 1p/19q codeletion, PCV chemotherapy is given before or after radiotherapy based on trials showing improved outcomes.
Panitumumab is a fully human monoclonal antibody that binds to the epidermal growth factor receptor (EGFR) with high affinity. It is approved as monotherapy or in combination with chemotherapy for wild-type KRAS metastatic colorectal cancer. Clinical trials have shown that panitumumab improves progression-free survival and overall survival when added to chemotherapy for first-line treatment of metastatic colorectal cancer patients with wild-type RAS tumors. Extended RAS testing beyond just KRAS exon 2 is important to identify patients most likely to benefit from panitumumab therapy. Common side effects include dermatological toxicities.
Management of recurrent Glioblastoma and role of BevacizumabAjeet Gandhi
1) Management of recurrent glioblastoma involves surgery, radiation, chemotherapy, targeted therapy or immunotherapy depending on the patient's condition and previous treatments.
2) Temozolomide combined with radiation is the standard initial treatment but recurrence is common. For recurrent glioblastoma, options include repeat surgery if the tumor is in a non-eloquent area, re-irradiation with stereotactic radiosurgery for small volumes, and nitrosourea chemotherapy.
3) Bevacizumab shows clinical activity as monotherapy for recurrent glioblastoma but its effect on overall survival is uncertain. Combining bevacizumab with lomustine improved progression-free survival compared to lomustine
Optimizing Chemotherapy For Malignant Gliomafondas vakalis
The document discusses optimizing chemotherapy for malignant glioma. Meta-analyses showed that combining temozolomide (TMZ) with radiotherapy improved survival rates compared to radiotherapy alone. A phase III trial demonstrated that concomitant and adjuvant TMZ with radiotherapy significantly improved progression-free and overall survival. Subset analyses found the benefit was consistent across patient subgroups. Methylation of the MGMT gene promoter was identified as predictive of benefit from TMZ therapy.
This document discusses innovations in the treatment of head and neck cancer, including molecular targeted therapies used with chemotherapy. It summarizes research showing that adding cetuximab, an anti-EGFR monoclonal antibody, to chemotherapy or radiotherapy improves survival rates for patients with locoregionally advanced or recurrent/metastatic squamous cell carcinoma of the head and neck compared to chemotherapy or radiotherapy alone. The document also reviews several clinical trials that have evaluated adding cetuximab to induction chemotherapy regimens or using it in combination with other targeted agents for these cancer types and stages.
This case study examines the use of cetuximab-based chemotherapy for the re-treatment of patients with metastatic colorectal cancer who had previously responded to cetuximab treatment but experienced disease progression after stopping treatment. The study aims to evaluate the overall response and safety of re-treating these patients with cetuximab-containing chemotherapy. It describes the study design, inclusion/exclusion criteria, experimental and control treatments, and primary/secondary outcome measures that will be assessed over a 2-year period.
Pembrolizumab - “Treatment of melanoma has never been this promising”Patwant Dhillon
Pembrolizumab is a monoclonal antibody that blocks the interaction between PD-1 receptors on T cells and PD-L1/PD-L2 ligands expressed by tumor cells. It was approved by the FDA based on results from the KEYNOTE-001 trial showing a 26% overall response rate in advanced melanoma patients who progressed on prior ipilimumab treatment. The trial found similar response rates of 26% for pembrolizumab doses of 2 mg/kg and 10 mg/kg every 3 weeks, with responses ongoing in 88% of patients after 8 months of follow up and a median progression free survival of 22 and 14 weeks respectively. Common adverse effects included fatigue, rash and pruritus.
Functional analysis of proteomic biomarkers and targeting glioblastoma stem c...Pasteur_Tunis
Présentation de Radovan Komel réalisée durant le cours du réseau international des instituts Pasteur de "Médecine Génomique: du diagnostic à la thérapie " (17-21 octobre 2016)
Mechanism of resistance to target therapyVito Lorusso
1. The document discusses resistance mechanisms to targeted kinase inhibitors (TKI) in metastatic renal cell carcinoma (mRCC).
2. Primary resistance is defined as a lack of response from the start of TKI therapy, while secondary resistance arises after an initial response followed by disease progression. Mechanisms of primary resistance include alternative pro-angiogenic pathways and non-angiogenic tumor growth.
3. Secondary resistance mechanisms include a new angiogenic wave induced by hypoxia, epithelial-to-mesenchymal transition, intratumoral heterogeneity, and gene mutations. Overcoming resistance may involve using non cross-resistant drugs that target pathways driving resistance.
This document discusses chemotherapy for gliomas. It begins by covering early trials of carmustine for glioblastoma in the 1960s. It then summarizes the landmark 2005 Stupp trial which showed improved survival with temozolomide combined with radiation therapy for newly diagnosed glioblastoma. The document also discusses trials of bevacizumab and other targeted therapies as well as immunotherapy approaches. It reviews treatment options for recurrent glioblastoma and anaplastic glioma. Finally, it briefly discusses chemotherapy approaches and trials for low-grade gliomas in both adults and children.
Erbitux is a monoclonal antibody used to treat metastatic colorectal cancer, non-small cell lung cancer, and head and neck cancer. It works by binding to epidermal growth factor receptors (EGFR) to inhibit tumor growth signals. Testing for mutations in the KRAS gene is important, as Erbitux is only effective for tumors with wild-type KRAS. Common side effects include skin rash and reactions to the intravenous infusion.
Chemotherapy is an important treatment option for both primary and secondary brain tumours. For primary brain tumours, temozolomide is often used in combination with radiation therapy for glioblastoma based on results from the landmark Stupp trial showing improved survival. Other drugs commonly used include carmustine, PCV regimen, platinum agents and targeted therapies such as bevacizumab are being investigated. Ongoing clinical trials are evaluating these agents in various settings and combinations to improve outcomes for brain cancer patients.
Dr. Patrick Hwu presents the latest information on immunotherapies for melanoma at the MRF's Patient Symposium at MD Anderson Cancer Center on January 31, 2015.
(1) The document summarizes the PORTEC 4A trial, which aims to evaluate molecular risk profiling to guide adjuvant treatment decisions in early-stage endometrial cancer.
(2) The trial compares adjuvant vaginal brachytherapy, the current standard, to a molecular profiling-based approach that may recommend observation, brachytherapy, or pelvic radiation.
(3) Based on previous studies, it is estimated that 50-55% of patients will be low risk and need only observation, 40% intermediate risk requiring brachytherapy, and 5-10% high risk needing pelvic radiation. The goal is to reduce overtreatment while maintaining local control.
Role of molecular targeted therapy in HCC DubaiPAIRS WEB
This document discusses hepatocellular carcinoma (HCC) and approaches to treating this growing clinical challenge. It provides background on HCC pathogenesis and prognostic factors such as tumor stage, liver function, and tumor biology. Treatment options including curative therapies for early stage disease and palliative options for advanced HCC are described. The role of the targeted therapy sorafenib in treating advanced HCC is summarized based on results from Phase III trials showing it can prolong both overall survival and time to progression compared to placebo. Ongoing research into additional targeted agents and combination approaches for HCC are also mentioned.
This document summarizes key findings from several studies related to acute myeloid leukemia (AML) in elderly patients:
1) A phase 3 trial found that azacitidine extended overall survival compared to conventional care regimens in older patients with newly diagnosed AML, with median OS of 10.4 months for azacitidine vs 6.5 months for conventional care.
2) Subanalyses found azacitidine provided particularly long OS benefits vs conventional care for patients with poor-risk cytogenetics (median OS 6.4 vs 3.2 months) or myelodysplasia-related changes (1-year OS 55.1% vs 31.3% for LDAC preselected
Diagnosing PM/DM is challenging due to rarity of the disease, their similar clinical presentation and the possibility of overlap syndromes. A comprehensive strategy for serological testing comprises of parallel determination of both MSA and MAA thereby reducing the time to diagnosis. Current immunoassays techniques (Immunoblot) targeting MAA & MSAs have –
The ability to include many parameters simultaneously which ensures higher detection rate; Become readily accessible & hence an opportunity for laboratories to contribute significantly in the disease diagnosis. MSA are highly specific for PM/DM, and many of them are also associated with a unique clinical subset of PM/DM, making them useful clinical diagnostic/prognostic biomarkers & continue to evolve.
This document summarizes the results of a clinical trial investigating the efficacy and safety of pembrolizumab (anti-PD-1 antibody) in patients with advanced melanoma that progressed after treatment with ipilimumab. The overall response rate was 26% in the 2 mg/kg group and 10% in the 10 mg/kg group, with responses ongoing after 1 year. Pembrolizumab demonstrated a manageable safety profile, with grade 3-4 drug-related adverse events occurring in 12% of patients. This trial provides evidence that pembrolizumab is an effective treatment option for patients with advanced melanoma who have progressed on ipilimumab.
1) High grade gliomas include grade III anaplastic astrocytomas, anaplastic oligodendrogliomas, and grade IV glioblastomas.
2) The standard of care for glioblastoma is maximal safe surgical resection followed by radiotherapy with concurrent and adjuvant temozolomide chemotherapy. Molecular markers like MGMT promoter methylation and IDH1 mutation provide prognostic information.
3) For anaplastic gliomas, the treatment involves surgical resection followed by radiotherapy. For anaplastic gliomas with 1p/19q codeletion, PCV chemotherapy is given before or after radiotherapy based on trials showing improved outcomes.
Panitumumab is a fully human monoclonal antibody that binds to the epidermal growth factor receptor (EGFR) with high affinity. It is approved as monotherapy or in combination with chemotherapy for wild-type KRAS metastatic colorectal cancer. Clinical trials have shown that panitumumab improves progression-free survival and overall survival when added to chemotherapy for first-line treatment of metastatic colorectal cancer patients with wild-type RAS tumors. Extended RAS testing beyond just KRAS exon 2 is important to identify patients most likely to benefit from panitumumab therapy. Common side effects include dermatological toxicities.
Management of recurrent Glioblastoma and role of BevacizumabAjeet Gandhi
1) Management of recurrent glioblastoma involves surgery, radiation, chemotherapy, targeted therapy or immunotherapy depending on the patient's condition and previous treatments.
2) Temozolomide combined with radiation is the standard initial treatment but recurrence is common. For recurrent glioblastoma, options include repeat surgery if the tumor is in a non-eloquent area, re-irradiation with stereotactic radiosurgery for small volumes, and nitrosourea chemotherapy.
3) Bevacizumab shows clinical activity as monotherapy for recurrent glioblastoma but its effect on overall survival is uncertain. Combining bevacizumab with lomustine improved progression-free survival compared to lomustine
Optimizing Chemotherapy For Malignant Gliomafondas vakalis
The document discusses optimizing chemotherapy for malignant glioma. Meta-analyses showed that combining temozolomide (TMZ) with radiotherapy improved survival rates compared to radiotherapy alone. A phase III trial demonstrated that concomitant and adjuvant TMZ with radiotherapy significantly improved progression-free and overall survival. Subset analyses found the benefit was consistent across patient subgroups. Methylation of the MGMT gene promoter was identified as predictive of benefit from TMZ therapy.
This document discusses innovations in the treatment of head and neck cancer, including molecular targeted therapies used with chemotherapy. It summarizes research showing that adding cetuximab, an anti-EGFR monoclonal antibody, to chemotherapy or radiotherapy improves survival rates for patients with locoregionally advanced or recurrent/metastatic squamous cell carcinoma of the head and neck compared to chemotherapy or radiotherapy alone. The document also reviews several clinical trials that have evaluated adding cetuximab to induction chemotherapy regimens or using it in combination with other targeted agents for these cancer types and stages.
This case study examines the use of cetuximab-based chemotherapy for the re-treatment of patients with metastatic colorectal cancer who had previously responded to cetuximab treatment but experienced disease progression after stopping treatment. The study aims to evaluate the overall response and safety of re-treating these patients with cetuximab-containing chemotherapy. It describes the study design, inclusion/exclusion criteria, experimental and control treatments, and primary/secondary outcome measures that will be assessed over a 2-year period.
Pembrolizumab - “Treatment of melanoma has never been this promising”Patwant Dhillon
Pembrolizumab is a monoclonal antibody that blocks the interaction between PD-1 receptors on T cells and PD-L1/PD-L2 ligands expressed by tumor cells. It was approved by the FDA based on results from the KEYNOTE-001 trial showing a 26% overall response rate in advanced melanoma patients who progressed on prior ipilimumab treatment. The trial found similar response rates of 26% for pembrolizumab doses of 2 mg/kg and 10 mg/kg every 3 weeks, with responses ongoing in 88% of patients after 8 months of follow up and a median progression free survival of 22 and 14 weeks respectively. Common adverse effects included fatigue, rash and pruritus.
Functional analysis of proteomic biomarkers and targeting glioblastoma stem c...Pasteur_Tunis
Présentation de Radovan Komel réalisée durant le cours du réseau international des instituts Pasteur de "Médecine Génomique: du diagnostic à la thérapie " (17-21 octobre 2016)
Mechanism of resistance to target therapyVito Lorusso
1. The document discusses resistance mechanisms to targeted kinase inhibitors (TKI) in metastatic renal cell carcinoma (mRCC).
2. Primary resistance is defined as a lack of response from the start of TKI therapy, while secondary resistance arises after an initial response followed by disease progression. Mechanisms of primary resistance include alternative pro-angiogenic pathways and non-angiogenic tumor growth.
3. Secondary resistance mechanisms include a new angiogenic wave induced by hypoxia, epithelial-to-mesenchymal transition, intratumoral heterogeneity, and gene mutations. Overcoming resistance may involve using non cross-resistant drugs that target pathways driving resistance.
This document discusses chemotherapy for gliomas. It begins by covering early trials of carmustine for glioblastoma in the 1960s. It then summarizes the landmark 2005 Stupp trial which showed improved survival with temozolomide combined with radiation therapy for newly diagnosed glioblastoma. The document also discusses trials of bevacizumab and other targeted therapies as well as immunotherapy approaches. It reviews treatment options for recurrent glioblastoma and anaplastic glioma. Finally, it briefly discusses chemotherapy approaches and trials for low-grade gliomas in both adults and children.
Erbitux is a monoclonal antibody used to treat metastatic colorectal cancer, non-small cell lung cancer, and head and neck cancer. It works by binding to epidermal growth factor receptors (EGFR) to inhibit tumor growth signals. Testing for mutations in the KRAS gene is important, as Erbitux is only effective for tumors with wild-type KRAS. Common side effects include skin rash and reactions to the intravenous infusion.
Safety and clinical activity of pembrolizumab for treatmentMarwa EL-Sayed
Pembrolizumab is a humanized monoclonal antibody that targets the PD-1 receptor. This study evaluated the safety and efficacy of pembrolizumab in 104 patients with recurrent or metastatic squamous cell carcinoma of the head and neck. The results showed that pembrolizumab had a manageable safety profile, with 63% of patients experiencing drug-related adverse events mostly grade 1-2. Pembrolizumab also demonstrated promising anti-tumor activity with an 18% overall response rate. Progression-free survival was 13 months. This study provides evidence that pembrolizumab is a potential new treatment option for this patient population.
Aim: to evaluate the effi cacy and tolerability of electro-hyperthermia (ET) for the treatment of relapsed malignant glioma.
Methods: this was a retrospective observational clinical study. Patients were included in the study if they had >18 years, informed consent signed, histological diagnosis of malignant glioma, failure of previous temozolamide-based chemotherapy and radiotherapy, indication for treatment with ET.
Hyperthermia was performed with short radiofrequency waves of 13.56 MHz using a capacitive coupling technique keeping the skin surface at 26 C°. The applied power ranged between 40-150 Watts and the calculated average equivalent temperature in the tumors was above 40 C° for more than 90% of the treatment duration (20-60 minutes gradually).
Stereotactic Radiotherapy of Recurrent Malignant Gliomas Clinical White PaperBrainlab
Learn more: https://www.brainlab.com/intraoperative-mri
Tumors of the central nervous system (CNS) represent approximately 176,000 newly diagnosed cases worldwide per year, with an estimated annual mortality of 128,000. Malignant gliomas comprise 30% of all primary CNS tumors and remain one of the greatest challenges in oncology today, despite access to state-of-the-art surgery, imaging, radiotherapy and chemotherapy.
Clinical Development of ADC Drugs Targeting TROP-2.pdfDoriaFang
TROP-2 is expressed in many tumor types, making it an emerging and popular target for ADC development. This article introduces clinical development of ADC drugs targeting TROP-2.
This document summarizes the role of cetuximab in treating squamous cell carcinoma of the head and neck (HNSCC). It discusses clinical trials that showed cetuximab improved survival when combined with radiation for locally advanced HNSCC and improved response rates compared to chemotherapy for recurrent/metastatic HNSCC. The document also reviews the mechanisms of action of cetuximab, potential biomarkers of response, common toxicities, and need for further research to better integrate cetuximab and identify patients most likely to benefit.
This document summarizes recent developments in molecular targeted therapies for head and neck cancer. It discusses two primary strategies - blocking EGFR signaling and angiogenesis pathways. Epidermal growth factor receptor (EGFR) is overexpressed in many head and neck cancers and associated with poorer outcomes. Cetuximab, an anti-EGFR monoclonal antibody, has shown efficacy in combination with radiation for locally advanced disease and in extending survival when added to chemotherapy for metastatic disease. Other targeted agents discussed include tyrosine kinase inhibitors and anti-angiogenic drugs.
Gastroenterology Medicine & Research-Crimson Publishers: Can we Optimize Immu...CrimsonGastroenterology
Immunotherapy is revolutionizing oncology, with a simple guiding principle: the host immune system has the potential to eradicate cancer, treatment consisting in optimizing immune actors' functions. Although significant results were demonstrated in patients with melanoma or lung cancer, objective response rate (ORR) is only 20% in digestive oncology. However, we can improve this situation by a better knowledge of anti-tumor immunity. For example, ORR is multiplied by two to three in case of PD-L1 (programmed death-ligand 1) overexpression or microsatellite instability (MSI). In a near future, we will certainly be able to take into account other biomarkers for building composite scores for assigning to each patient with digestive cancer an 'immune identity card' able to strongly predict immunotherapy efficacy.
Low grade glioma evidence based managementGaurav Kumar
Management of low grade gliomas (LGG) focuses on the WHO grading system and risk stratification. Current trends include:
1. Immediate postoperative radiotherapy (PORT) for high risk LGG with residual tumor >1cm, preop size >4cm, or age >40 based on improved progression free survival shown in clinical trials.
2. A PORT dose of 54Gy in 30 fractions is recommended based on Phase III trials showing no benefit to higher doses.
3. Adjuvant chemotherapy like temozolomide may be considered for high risk patients, especially those with 1p/19q codeletions and IDH1/2 mutations, though radiotherapy remains standard of
This document discusses monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM), which are precursor states of multiple myeloma. It provides definitions and risk factors for progression from MGUS to myeloma. Genetic and molecular insights into disease progression are explored, including primary and secondary genetic events. Management strategies for MGUS and SMM are reviewed, including risk stratification and criteria for high-risk SMM. Ongoing research into clonal evolution and the tumor microenvironment shed light on myelomagenesis. The first randomized trial to show a benefit of early treatment in high-risk SMM is summarized.
The document discusses a clinical trial comparing the monoclonal antibodies obinutuzumab and rituximab for treating diffuse large B-cell lymphoma. Obinutuzumab is a glycoengineered, humanized antibody that clusters the CD20 antigen more effectively than rituximab. In a phase III trial, obinutuzumab plus chemotherapy did not significantly improve progression-free survival over rituximab plus chemotherapy. However, obinutuzumab's glycoengineering may enhance its antibody-dependent cellular cytotoxicity and direct cell death mechanisms relative to rituximab.
Yan Carlos Vargas Caycho
Pediatric Malignant Gliomas
Radioterapia en Gliomas de Alto Grado en Pediatria
Radioterapia en Glioblastoma Multiforme
Radioterapia en Astrocitoma Anaplasico
Radioterapia en Tumores del Sistema Nervioso Central
This document discusses chemotherapy options for treating metastatic melanoma. It summarizes a study that compared the effectiveness of Temozolomide alone or in combination with interferon or thalidomide for metastatic melanoma. The study found that all three regimens were well-tolerated and had comparable efficacy, with combination therapies showing potential for better tumor response and survival. Specifically, the combination of Temozolomide and thalidomide seemed the most promising. However, chemotherapy overall has limited effectiveness for melanoma, responding in only about 14% of patients. Alternative treatment options like radiosurgery are also discussed.
1) The document discusses Targovax's clinical programs targeting cancer through immune activation, including their ONCOS oncolytic virus and TG RAS neoantigen vaccine.
2) Early clinical trials of ONCOS-102 demonstrated immune activation and clinical activity in patients with various solid tumors.
3) Targovax is conducting additional trials of ONCOS-102 in combination with checkpoint inhibitors in indications like mesothelioma and peritoneal cancers.
4) The TG vaccine targets mutated RAS neoantigens, which are present in many cancer types, and aims to induce T-cell responses against patient-specific tumors.
This document discusses the use of pharmacogenomics for personalized medicine. It defines key terms like pharmacogenomics and pharmacogenetics. It describes how genetic variations can be identified and linked to differences in drug response and phenotypes. Specific examples are given of actionable genotypes for warfarin and codeine metabolism. Challenges and opportunities for further research in implementing pharmacogenomics in clinical practice are also outlined.
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3. Radiotherapy plus nimotuzumab or placebo in the
treatment of high grade glioma patients: results
from a randomized, double blind trial
Maria Teresa Solomó1
Email: maisol@infomed.sld.cu
Julio César Selva2
Email: selva@hcqho.hlg.sld.cu
Javier Figueredo3
Email: javierfm@infomed.sld.cu
José Vaquer4
Email: jose.vaquer@infomed.sld.cu
Carolina Toledo5
Email: carolina.toledo@infomed.sld.cu
Nelson Quintanal6
Email: nelson.quintanal@infomed.sld.cu
Silvia Salva7
Email: aperez@infomed.sld.cu
Rafael Domíngez8
Email: rafael.dominguez@infomed.sld.cu
José Alert9
Email: jalert@infomed.sld.cu
Jorge Juan Marinello9
Email: soconcol@infomed.sld.cu
Mauricio Catalá3
Email: mauricio.catala@infomed.sld.cu
Martha González Griego10
Email: martha.griego@infomed.sld.cu
Juan Antonio Martell10
Email: juanantonio@cencec.sld.cu
Patricia Lorenzo Luaces11
Email: patricial@cim.sld.cu
Javier Ballesteros12
Email: javier.ballesteros@ehv.es
4. Niurys de-Castro13
Email: niurys@ifal.uh.edu.cu
Ferdinand Bach14
Email: fbach@oncoscience-ag.de
Tania Crombet11*
*
Corresponding author
Email: taniac@cim.sld.cu
1
Calixto García Hospital, Havana, Cuba
2
Lucía Iñiguez Hospital, Holguin, Cuba
3
Center for Medical and Surgical Research, Havana, Cuba
4
Arnaldo Milián Hospital, Santa Clara, Cuba
5
Maria Curie Hospital, Havana, Cuba
6
Luis Díaz Soto Hospital, Havana, Cuba
7
Hermanos Ameijeiras Hospital, Havana, Cuba
8
Saturnino Lora Hospital, Santiago de Cuba, Cuba
9
National Institute of Oncology and Radiobiology, Havana, Cuba
10
National Center for Clinical Trials, Havana, Cuba
11
Center of Molecular Immunology, PO BOX 16040, Havana 11600, Cuba
12
University of the Basque Country, Havana, Spain
13
Institute of Pharmacy and Food, Havana, Cuba
14
Oncoscience AG, Wedel, Germany
Abstract
Background
The prognosis of patients bearing high grade glioma remains dismal. Epidermal Growth
Factor Receptor (EGFR) is well validated as a primary contributor of glioma initiation and
progression. Nimotuzumab is a humanized monoclonal antibody that recognizes the EGFR
extracellular domain and reaches Central Nervous System tumors, in nonclinical and clinical
setting. While it has similar activity when compared to other anti-EGFR antibodies, it does
not induce skin toxicity or hypomagnesemia.
5. Methods
A randomized, double blind, multicentric clinical trial was conducted in high grade glioma
patients (41 anaplastic astrocytoma and 29 glioblastoma multiforme) that received
radiotherapy plus nimotuzumab or placebo. Treatment and placebo groups were well-
balanced for the most important prognostic variables. Patients received 6 weekly doses of 200
mg nimotuzumab or placebo together with irradiation as induction therapy. Maintenance
treatment was given for 1 year with subsequent doses administered every 3 weeks. The
objectives of this study were to assess the comparative overall survival, progression free
survival, response rate, immunogenicity and safety.
Results
The median cumulative dose was 3200 mg of nimotuzumab given over a median number of
16 doses. The combination of nimotuzumab and RT was well-tolerated. The most prevalent
related adverse reactions included nausea, fever, tremors, anorexia and hepatic test alteration.
No anti-idiotypic response was detected, confirming the antibody low immunogenicity. The
mean and median survival time for subjects treated with nimotuzumab was 31.06 and 17.76
vs. 21.07 and 12.63 months for the control group.
Conclusions
In this randomized trial, nimotuzumab showed an excellent safety profile and significant
survival benefit in combination with irradiation.
Trial registration
Cuban National Register for clinical trials (No. 1745) (http://registroclinico.sld.cu/ensayos).
Keywords
High grade glioma (HGG), Nimotuzumab, EGFR, Monoclonal antibody, Adult glioma,
Anaplastic astrocytoma, Glioblastoma multiforme
Background
High-grade gliomas (HGG) are the most common primary tumors in the central nervous
system (CNS) in adults [1]. Despite remarkable advances in cancer research and in
neurosurgery, radiotherapy and chemotherapy, these patients still face a poor prognosis,
pointing towards an urgent need for new therapeutic approaches [2]. Standard treatment for
HGG usually entails surgery followed by radiotherapy plus chemotherapy. Temozolomide is
the drug of choice since 2005 for glioblastoma multiforme (GBM) patients [3], but
unfortunately, it is not available in Cuba, due to the commercial restrictions imposed by the
US embargo. However, since the survival benefit of radio-chemotherapy is so limited [4],
patients with brain tumors are considered candidates for clinical trials that evaluate new
drugs, radiosensitizers or new accelerated/hyperfractionated radiation schemes. Therefore, we
decided to evaluate the efficacy of radiation plus an anti-EGFR antibody vs. radiation plus
6. placebo in a controlled double blind trial, in newly diagnosed patients with grade III/IV
astrocytomas.
The Epidermal Growth Factor Receptor (EGFR) is a membrane-bound receptor that has been
shown to have a major role in the pathogenesis and progression of different cancers [5].
EGFR is greatly expressed in HGG patients and gene amplification represents one of the
most frequent alterations in this tumor type [6]. Moreover, EGFR plays a fundamental role in
gliomagenesis. According Mazzoleni and co-workers, cancer stem cells (CSC) isolated from
glioma patients, need to express EGFR to promote experimental tumorigenesis and EGFR-
expressing initiating cells display the most malignant phenotype [7]. In summary, EGFR is
well validated as a primary contributor of HGG initiation and progression [8].
Nimotuzumab is a humanized monoclonal antibody that recognizes the EGFR extracellular
domain. The antibody was obtained by humanization of the murine antibody ior egf/r3 [9].
Because nimotuzumab has a 10 fold lower affinity to the EGFR, as compared to cetuximab,
its capacity to bind EGFR is heavily dictated by cell receptor density [10]. Nimotuzumab
preclinical and clinical characterizations have been summarized before [11-13].
A distinguishing feature of nimotuzumab compared to other mAbs of the EGFR class, is the
lack of severe skin toxicity as well as severe hypomagnesemia [14]. Two hypotheses have
been posed to explain this lack of skin toxicity of nimotuzumab: according Garrido [10],
nimotuzumab requires bivalent binding for stable attachment to the cellular surface, leading
to selectively binding to cells that express moderate to high EGFR levels. Accordingly,
nimotuzumab will selectively target tumors, and not normal tissues. Instead, Talavera built a
computer model of the nimotuzumab-EGFR complex [15], where nimotuzumab blocks
ligand binding, but allows the receptor to adopt its active conformation, warranting the basal
level of signaling needed for the survival of non-tumor cells [15].
This type of binding is analogous to the binding of trastuzumab to the HER-2 receptor [16].
Nimotuzumab safety profile permits up to 800 mg doses in adults [17] or 150–250 mg/m2 in
children, without safety concerns [13].
In the nonclinical setting, nimotuzumab has been evaluated in the glioma cell line U87MG.
Co-administration of the antibody with radiation increased the radiosensitivity, resulting in a
delay of tumor growth. The antibody reduced angiogenesis and the total number of
radioresistant cancer stem cells [18].
In a separate study, nude mice that had an intra-cerebral implant of the U87MG cell line were
treated with nimotuzumab labelled with 111
Indium. Radioactivity was measured after organ
explantation. Results showed a clear time-dependant increase in 111
indium nimotuzumab
uptake in the tumour in contrast to all other organs [19].
The capacity of the antibody of crossing the blood–brain barrier (BBB) was studied also by
radioimmunscitigraphy using nimotuzumab labelled with Technetium 99 (Tc99). In a phase
I/II trial, immunscitigraphy done after radiation plus nimotuzumab, showed a positive MAb
uptake by patients with tumors, while subjects with complete responses showed no antibody
accumulation at the known site of tumors [20]. In addition, it has been proposed that in the
fast-growing gliomas, the newly formed blood vessels lack BBB function. As a consequence,
MAbs such as nimotuzumab may primarily enter a brain tumor through tumor vessels that
lack BBB [21,22].
7. To conclude, the nonclinical and clinical radiolabelled study does support penetration of the
brain. MRI scan results in children with refractory brain tumors treated with nimotuzumab
alone also provided evidence of nimotuzumab activity at the tumor site [13].
An open labeled study of the combination nimotuzumab plus radiotherapy
(RT)/temozolomide (TMZ) study was conducted in Germany in 149 adult patients with
newly diagnosed GBM [23]. In this paper, we report the results of a randomized, double blind
clinical trial where 70 HGG patients were treated with irradiation plus nimotuzumab or
placebo.
Methods
A randomized, double-blind, multicentric, Phase II clinical trial was conducted in 70 HGG
patients that received irradiation plus either nimotuzumab or a placebo. Sample size was
calculated by anticipating a 6-month improvement in median survival time with respect to the
baseline survival in the control group. The sample size was calculated using a “sample size
calculation” software, Version 1.1, option 4: comparison of two means, from the Institute of
Medical Research in Barcelona.
Patients were recruited at 8 clinical sites. They were subjected to maximal excision (total,
partial resection or biopsy) at least 4 weeks before the inclusion and were candidates of
radiotherapy. Other important inclusion criteria included: age older than 18, Karnofsky
performance status (KPS) ≥ 60 and adequate bone marrow, liver and renal function; subjects
in fertile age were required to possess a negative pregnancy test and to use an effective
contraceptive method. The primary objective of this study was to assess the overall survival
(OS) of nimotuzumab in HGG patients when compared to the control group receiving
irradiation and placebo. The secondary objectives were to assess progression-free survival
(PFS), response rate and the safety and immunogenicity of nimotuzumab in this patient
population. Eligible patients were randomized to either group in a 1:1 ratio.
Random assignment was performed centrally through a validated simple randomization
system version 1.2. Patients were previously stratified by histology (GBM vs. AA) to ensure
equal distribution in both groups. The study was designed to include up to 30 GBM patients
while the rest were AA patients. Treatment dose was 200 mg of nimotuzumab, intravenously
infused over 30 to 60 minutes. The control group received 4 vials of a placebo composed by a
saline buffer. Each subject received a weekly infusion, for 6 weeks, concurrently with the
radiotherapy. After finishing induction therapy, patients received, in double blind fashion, a
maintenance dose of 200 mg of nimotuzumab or 4 vials of placebo every 21 days until
completing 1 year of treatment.
Irradiation was delivered in doses of 180–200 cGy given once daily, 5 days per week, to a
total dose of 5000 cGy to 6000 cGy. Radiotherapy planning and simulation was performed on
the basis of recent CT scans. The irradiation field encompassed the initial tumor volume plus
a security margin of 2 cm.
Before each dose, a physical examination of the major body systems was conducted. Vital
signs were measured before and after each infusion. Hematology and biochemistry tests were
carried out previous to the first dose and every 14 days for 6 weeks. Later on, sampling was
carried out every 21 days, until 1 year of study.
8. Adverse events were assigned severity/intensity categories according the Common
Terminology Criteria for Adverse Events (CTCAE) version 3. The anti-idiotypic response
against nimotuzumab, was measured in 12 patients through an indirect ELISA system
validated at the Center of Molecular Immunology, that has been previously described [20].
For response evaluation, nuclear magnetic resonance (MRI) or CT-scans were done before
inclusion and then, every 3 months. Response was classified according to WHO modified
criteria. Overall survival and progression free survival were analyzed using the Kaplan-Meier
method and the parametric Weibull regression survival model [24]. The Weibull Shape
Parameter (WSP) test is very powerful at detecting signals that occur shortly after starting
treatment [24].
The trial was performed in compliance with the Helsinki Declaration. The protocol was
approved by the Institutional Review Boards of the 8 research sites: Calixto García Hospital,
Lucía Iñiguez Hospital, Center for Medical and Surgical Research, Arnaldo Milián Hospital,
Maria Curie Hospital, Luis Díaz Soto Hospital, Hermanos Ameijeiras Hospital and Saturnino
Lora Hospital, as well as by the National Regulatory Authority: the State Centre for Drug
Quality Control. All patients signed the informed consent form. The protocol information was
included on the National Register for clinical trials (No. 1745) which is a primary register
approved by the World Health Organization (WHO) (http://registroclinico.sld.cu/ensayos).
Results
A total of 73 patients were included in the study: 43 patients with Anaplastic Astrocytoma
(AA) and 30 patients with Glioblastoma Multiforme (GBM). Three patients from the
nimotuzumab arm (10, 54 and 61) abandoned the study from inclusion and did not receive
any therapy. Information was available from 70 subjects: 41 AA and 29 GBM patients. In the
AA group, 41 patients were analyzed per intention to treat: 23 received placebo and 18
received nimotuzumab. In the GBM group, 29 patients were analyzed, 15 of these received
placebo and 14 received nimotuzumab.
The trial started on June 2005 and was completed on June 2010. Baseline characteristics are
described in Table 1.
9. Table 1 Patient demographic and tumor characteristics
Variables Number of patients Number of patients
(%) (%)
Control group Nimotuzumab patients
Sex
Male 19 (50%) 21 (65.6%)
Female 19 (50%) 11 (34.4%)
Race
White 31 (81.5%) 27 (84.3%)
Black 1 (2.6%) 2 (6.3%)
Mixed 6 (15.8%) 3 (9.3%)
Age
Mean 45.5 47.2
Median 46.5 44
Grouped age
Younger than 50 21 (55.3%) 19 (59.4%)
Older than 50 17 (44.7%) 13 (40.6%)
Body weight
Mean 68.1 kg 69 kg
Median 65 kg 70 kg
Histology
AA 23 (60.5%) 18 (56.2%)
GBM 15 (39.5%) 14 (43.7%)
KPS
100 8 (21%) 9 (28.1%)
90 9 (23.6%) 10 (31.2%)
80 6 (15.8%) 8 (25%)
70 11 (28.9%) 2 (6.2%)
60 4 (10.5%) 3 (9.3%)
Previous surgery
Total 2 (5.4%) 5 (17.2%)
Partial 27 (72.9%) 14 (48.2%)
Biopsy 8 (21.6%) 10 (34.5%)
The groups were balanced for the most important prognostic features: histology, age, surgical
intervention and KPS. In total, 32 patients received nimotuzumab and RT while 38 patients
were treated with irradiation and a placebo. Nimotuzumab group received an average dose of
2631 mg, although the median cumulative dose was 3300 mg. The maximal administered
dose was 3600 mg. The median number of doses was 16. Concerning radiotherapy, the mean
cumulative dose was 5556 cGy.
The combination of nimotuzumab and RT was well-tolerated. More than 85% of the adverse
events in either group were categorized as grade 1 or 2 (mild or moderate), according the
CTCAE scale. Of these, only 15% were adverse reactions, which are, causally linked to
nimotuzumab. No dose reduction was required as a consequence of an adverse event. In the
10. placebo arm, the most frequent adverse events consisted on headache, seizures, dry
radiodermitis, fever, asthenia, alopecia and alteration of the liver function tests.
In the nimotuzumab arm, the most common adverse reactions included nausea, tremors,
anorexia, increase of the liver function parameters and fever. The most frequent adverse
events unrelated to treatment were headache, alopecia, seizures and radiodermitis. Overall,
serious adverse events included headache, vomiting, seizures, brain edema, pneumonia,
hemiparesis, motor defects, disorientation, respiratory depression and intracranial
hypertension. All serious adverse events were attributed to the natural course of the disease
and the neurological worsening associated with HGG. None of the serious adverse events
were attributed to nimotuzumab. Table 2 summarizes the most frequent unrelated and related
toxicities for both treatment groups.
Table 2 Most frequent unrelated and related adverse events after treatment with
irradiation plus nimotuzumab or placebo
Adverse event Placebo arm Nimotuzumab arm
Number of events Number of events
Unrelated (Not related and unlikely)
Headache 42 17
Seizures 16 6
Dry radiodermitis 6 5
Fever 6
Asthenia 5 4
Liver function tests alterations 7 5
Alopecia 4 7
Possibly, probably or definitively related with nimotuzumab
Liver function tests alterations 8
Nauseas 4
Tremors 3
Anorexia 3
Fever 2
None of these patients developed anti-idiotypic response against the murine residues of the
humanized molecule.
Antitumor response was confirmed for 33 patients in the AA stratum (17 controls and 16
nimotuzumab treated subjects) and 20 patients in the GBM arm (9 controls and 11 antibody
treated subjects). No significant differences were detected between the 2 groups in relation to
overall response or disease control rate. Objective response was 59.25% for nimotuzumab
and 53.84%, for the placebo arm. Disease control rate was 85.18% for the active drug group
vs. 84.61%, in the placebo cohort.
The mean and median survival time for the intent to treat (ITT) population in the
nimotuzumab cohort was 31.06 and 17.76 months, and 21.07 and 12.63 months for those
patients treated with placebo and irradiation (HR=0,64). This difference was statistically
significant according the Weibull parametric model (Weibull statistics, p = 0.032).
11. For AA patients, the mean and median survival time was 41.29 and 44.56 months, if they
received nimotuzumab vs. 29.67 and 17.56 months for the control patients (Weibull statistics,
p = 0.311). For the GBM patients, mean and median overall survival corresponded to 17.24
and 8.40 (nimotuzumab arm) vs. 9.84 and 8.36 months (placebo arm), respectively (Weibull
statistics, p = 0.026).
PFS was evaluated as a secondary endpoint. In the ITT analysis, the mPFS was 15.73 months
for nimotuzumab + RT and 6.5 months for the control arm. Overall survival and Progression
free survival curves for the whole population are illustrated at Figure 1. Figure 2 presents the
survival curves according histology.
Figure 1 Overall survival and Progression Free survival of patients treated with
radiotherapy and nimotuzumab or placebo.
Figure 2 Overall survival of GBM and AA patients treated with radiotherapy and
nimotuzumab or placebo.
Discussion
Eventhough, chemo-radiotherapy is the standard of care for anaplastic astrocytomas and
glioblastoma multiforme, patients’ prognosis remains very poor and the disease is still
incurable. Thus, enrolling this patient population in clinical trials that evaluate new drug
candidates is a very appealing strategy. Novel biologic therapies under clinical evaluation for
patients with high grade glioma include dendritic cell vaccination, tyrosine kinase receptor
inhibitors, farnesyl transferase inhibitors, viral-based gene therapy, oncolytic viruses,
vascular endothelial growth factor inhibitors and Epidermal growth factor-receptor inhibitors
[25,26]. This manuscript illustrates the results of combining irradiation and an anti-EGFR
antibody in a double blind trial that complements the nimotuzumab add-on to
temozolomide/irradiation study in GBM, which is underway under a German sponsorship in
Europe [23].
Nimotuzumab was very well tolerated and the most frequent adverse reactions consisted of
grade 1/2 infusion reactions. Remarkably, patients received a cumulative dose of 3300 mg,
which is much higher than the dose administered in the previous Phase I trial (1200 mg) and
is probably the highest cumulative antibody dose ever administered to glioma patients. After
16 doses of nimotuzumab, there was no increasing toxicity with repeated treatment. Radiation
associated toxicity was not exacerbated by the antibody. As reported in all previous studies,
nimotuzumab did not induce skin rash [11-13,20,27 and 28]. No anti-idiotypic response was
detected, confirming nimotuzumab low immunogenicity.
Several EGFR inhibitors have been used to treat HGG patients [29-42]. Cetuximab was
administered as monotherapy to recurrent glioma patients with an acceptable safety profile
[30]. The most frequent adverse events have been acne-like rash (folliculitis/dermatitis)
together with xerodermia, paronichia, fissures at the hands and/or feet, dermatitis of the
eyelids, and increased facial hair growth [30]. Alternatively, small tyrosine kinase inhibitors
have been used to treat recurrent or newly diagnosed glioma patients. More than 10 clinical
trials using erlotinib or gefitinib, have been reported [31-42]. Globally, both drugs were well
tolerated, being diarrhea and rash the most common toxicity. The majority of these events
were mild or moderate, while grade 3 or higher events were reported in one-third of the
12. patients receiving erlotinib in the recurrent scenario [31-36]. Strikingly, one trial evaluating
the combination of temozolomide, radiotherapy and erlotinib was discontinued due to
unacceptable toxicity [39].
Regarding clinical outcome, patients achieved a significant improvement in overall survival,
if they received nimotuzumab and irradiation. However, this result should be interpreted with
caution since even though no significant differences were detected between the 2 groups
regarding the most important prognostic factors, more patients with poorer KPS and no
debulking surgery were included to the control group.
Nimotuzumab has been evaluated before in combination with irradiation and temozolimide
for the treatment of newly diagnosed GBM patients. In a trial conducted at 11 hospitals in
Germany, patients were randomized to arm A (nimotuzumab/RT/TMZ) versus arm B
(RT/TMZ). Results demonstrated a median overall survival (MOS) of 22.3 and 19.6 months
for groups A and B that were comparable with the results of Hegi of 21.7 (RT/TMZ) vs. 15.3
months (RT) for patients with methylated MGMT [24], and better than Stupp’s of 14.6
(RT/TMZ) and 12.1 months (RT) [3] or Hegi, for patients with unmethylated MGMT of 12.7
(RT/TMZ) vs. 11.8 months (RT) [43]. Patients with non-methylated MGMT derived the
greatest benefit after treatment with nimotuzumab: MOS, 19.6 months (arm A) vs 15.0
months (Arm B) [23]. The authors concluded that nimotuzumab shows a clear trend towards
efficacy in MGMT non-methylated glioblastoma patients together with an excellent safety
profile [23]. Our finding is comparable to the results of the German Phase III study, where
the combination of nimotuzumab/RT/TMZ showed the greatest advantage over RT/TMZ in
the subset of patients with non-methylated MGMT, who are resistant to the alkylating agent,
via direct DNA repair [43]. Nimotuzumab didn’t significantly improve the rates of objective
response or disease control. However, it increases PFS and overall survival, demonstrating its
predominant cytostatic effect and its role in controlling the tumor progression rate.
Overall, patients achieved a lower survival than reported for AA and GBM, particularly if
treated with placebo. This poor outcome can be explained by the baseline characteristics of
the patient population: 29 patients (41.4%) were older than 50, 20 patients (28.6%) had a
KPS of 60 or 70, 18 patients (25.7%) had just a biopsy, while only 7 patients (10%) got a
gross tumor resection. Lower KPS, lack of debulking surgery and older ages are strong
predictors of poor outcome, according the recursive portioning analysis proposed by RTOG
and validated by EORTC [44,45].
So far, other EGFR antagonists have resulted in limited clinical activity in glioma patients
[29-42]. Cetuximab has a low single-agent activity in patients with recurrent HGG [30].
Furthermore, erlotinib, when used in the recurrent setting has shown to be marginally
beneficial [31-37]. For the newly diagnosed patients, erlotinib co-administered with
radiotherapy and temozolomide was not efficacious [39]. We speculate that the lack of
efficacy of other EGFR antagonists might be associated with reduced drug exposure.
Treatment with cetuximab, erlotinib and gefitinib were maintained as long as there were no
unacceptable safety concerns or until disease progression. Since these EGFR antagonists can
induce severe acne-like rash toxicity, hypomagnesia and diarrhea, toxicity might have
prevented protracted therapy.
13. Conclusions
In this randomized, double blind, placebo-controlled trial, nimotuzumab continues to show an
excellent safety profile (consistent with an international pharmacovigilance data base of
17,451 patients), and survival benefit in patients with high grade glioma in combination with
irradiation.
Abbreviations
AA, Anaplastic Astrocytoma; CT scan, Computer Tomography; CTC, Common Toxicity
Criteria; EGFR, Epidermal Growth Factor Receptor; EORTC, European Organization for
Research and Treatment of Cancer; GBM, Glioblastoma Multiforme; HGG, High Grade
Glioma; KPS, Karnofsky Performance Status; MOS, Median overall survival; MRI, Magnetic
Resonance Image; OS, Overall survival; PFS, Progression Free Survival; RT, Radiotherapy;
RTOG, Radiation Therapy Oncology Group; TMZ, Temozolomide
Competing interests
All authors declare that they have no competing interests.
Author’s contributions
MTS was the principal investigator of the clinical trial; JCS, JF, JV, NQ, SS, RD and CT
were the principal investigators of the 7 other hospitals that took part in the multicentric
study, JA and JJM and MC were the radiotherapists that irradiated the patients, MGG and
JAM were the clinical research assistants that conducted the study, PLL and JB made the
statistical analysis, NC evaluated the HAMA the response, FB made significant contributions
to the elaboration and revision of the manuscript and TC was the project leader. All authors
reviewed and approved the final version of the manuscript prior to its submission for
publication
Author’s information
Patricia Lorenzo Luaces and Tania Crombet are employees of the Center of Molecular
Immunology, the research institution that patented and manufactures nimotuzumab.
Ferdinand Bach works for Oncoscience AG, Wedel, a company that owns nimotuzumab
marketing rights in Europe. The present study was sponsored by the Center of Molecular
Immunology, Havana, Cuba and The Cuban Ministry of Health.
Acknowledgments
We acknowledge the assistance of the clinical research coordinators, nurses, radiotherapist,
radiologists and pharmacists from the 8 clinical sites that participated in the study. We thank
our patients and relatives for their unconditional support.
14. Funding
The study was sponsored by the Center of Molecular Immunology, Havana, Cuba and The
Cuban Ministry of Health.
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20. Overal survivall (GBM) Overall survival (AA)
P a t i e n t s a t r i s k 0 1 0 2 0 3 0 4 0 5 0 P a t i e n t s a t r i s k 0 1 0 2 0 3 0 4 0 5 0
n i m o t u z u m a b 1 4 7 3 3 n i m o t u z u m a b 1 8 1 4 1 0 8 7 4
c
o n t r o l 1 5 6 1
c
o n t r o l 2 3 1 5 9 6 5
Figure 2