GenesisCare adquiere el grupo andaluz Oncosur
SUR.
21 septiembre
El grupo australiano GenesisCare da un nuevo impulso a su negocio en España ( IMOncology) con la adquisición del 100% del grupo andaluz Oncosur y de sus cinco clínicas oncológicas en Andalucía, sitas en Córdoba, Granada, Jerez, Campo de Gibraltar (Algeciras), además de un centro de oncología veterinaria en Cabra (Córdoba). Oncosur, con sede en Málaga, está integrado por las sociedades Oncología del Sur, Mediklab Medical Solutions y Clínica Radon, controladas hasta ahora por las familias Recio y Sacchetti (el equipo directivo seguirá al frente del grupo, tras la transacción).
viernes, 30 de septiembre de 2016
Nivolumab: FDA Modifies the Dosage Regimen for Currently Approved Indications for Nivolumab
FDA Modifies the Dosage Regimen for Currently Approved Indications for Nivolumab
New recommended regimen is 240 mg i.v. every two weeks until disease progression or intolerable toxicity
Date: 29 Sep 2016
Topic: Genitourinary cancers / Melanoma / Lung and other thoracic tumours / Anticancer agents & Biologic therapy
On 13 September, 2016, the US Food and Drug Administration (FDA) modified the dosage regimen for nivolumab (Opdivo, Bristol-Myers Squibb Co.) for the currently approved indications for renal cell carcinoma, metastatic melanoma, and non-small cell lung cancer (NSCLC). The currently approved recommended dosage regimens were modified to 240 mg intravenously (i.v.) every two weeks.
The approval modifies the Dosage and Administration section of the labelling by replacing the single dose regimen of nivolumab (3 mg/kg intravenously every two weeks) with the new recommended regimen of 240 mg i.v. every two weeks until disease progression or intolerable toxicity for renal cell carcinoma, metastatic melanoma, and NSCLC.
In addition, the nivolumab dosing regimen in combination with ipilimumab for melanoma will remain the same (nivolumab 1 mg/kg i.v., followed by ipilimumab on the same day, every 3 weeks for 4 doses). However, after completion of ipilimumab, the recommended nivolumab dose will be 240 mg every two weeks until disease progression or intolerable toxicity.
The recommended dose for classical Hodgkin lymphoma remains 3 mg/kg i.v., every 2 weeks until disease progression or intolerable toxicity.
The approval was based on population pharmacokinetics analyses and dose/exposure-response analyses demonstrating the comparability of the pharmacokinetics exposure, safety, and efficacy of the proposed new dosing regimen with the previously approved regimen.
Based on simulations by the population pharmacokinetics model, FDA determined that the overall exposure at 240 mg every two weeks flat dose is similar (less than 6% difference) to 3 mg/kg every two weeks. These differences in exposure are not likely to have a clinically meaningful effect on safety and efficacy, since dose/exposure response relationships appear to be relatively flat in these three indications.
Full prescribing information is available here
New recommended regimen is 240 mg i.v. every two weeks until disease progression or intolerable toxicity
Date: 29 Sep 2016
Topic: Genitourinary cancers / Melanoma / Lung and other thoracic tumours / Anticancer agents & Biologic therapy
On 13 September, 2016, the US Food and Drug Administration (FDA) modified the dosage regimen for nivolumab (Opdivo, Bristol-Myers Squibb Co.) for the currently approved indications for renal cell carcinoma, metastatic melanoma, and non-small cell lung cancer (NSCLC). The currently approved recommended dosage regimens were modified to 240 mg intravenously (i.v.) every two weeks.
The approval modifies the Dosage and Administration section of the labelling by replacing the single dose regimen of nivolumab (3 mg/kg intravenously every two weeks) with the new recommended regimen of 240 mg i.v. every two weeks until disease progression or intolerable toxicity for renal cell carcinoma, metastatic melanoma, and NSCLC.
In addition, the nivolumab dosing regimen in combination with ipilimumab for melanoma will remain the same (nivolumab 1 mg/kg i.v., followed by ipilimumab on the same day, every 3 weeks for 4 doses). However, after completion of ipilimumab, the recommended nivolumab dose will be 240 mg every two weeks until disease progression or intolerable toxicity.
The recommended dose for classical Hodgkin lymphoma remains 3 mg/kg i.v., every 2 weeks until disease progression or intolerable toxicity.
The approval was based on population pharmacokinetics analyses and dose/exposure-response analyses demonstrating the comparability of the pharmacokinetics exposure, safety, and efficacy of the proposed new dosing regimen with the previously approved regimen.
Based on simulations by the population pharmacokinetics model, FDA determined that the overall exposure at 240 mg every two weeks flat dose is similar (less than 6% difference) to 3 mg/kg every two weeks. These differences in exposure are not likely to have a clinically meaningful effect on safety and efficacy, since dose/exposure response relationships appear to be relatively flat in these three indications.
Full prescribing information is available here
martes, 27 de septiembre de 2016
Basal Cell Carcinoma: Vismodegib Review Supports Use in Locally Advanced, Metastatic BCC
Vismodegib Review Supports Use in Locally Advanced, Metastatic BCC
Vismodegib treatment benefits confirmed for locally advanced and metastatic basal cell carcinoma
Date: 27 Apr 2016
Author: By Lynda Williams, Senior medwireNews Reporter
Topic: Anti-Cancer Agents & Biologic Therapy / Melanoma and other Skin Tumours
medwireNews: Systematic review and pooled analysis add further support for use of the hedgehog pathway inhibitor (HPI) vismodegib in patients with locally advanced and metastatic basal cell carcinoma (la/mBCC).
“Vismodegib was identified to have a significant, consistent effect on the median duration of therapy of laBCC and mBCC”, say John Strasswimmer and co-workers from the University of Miami Miller School of Medicine in Florida, USA.
“While mBCC responses are superior to any traditional approach, the response rate for laBCC might be considered in the context of other standard treatment options including surgery and radiation therapy”, they write in JAMA Dermatology.
The team collated information from eight studies of vismodegib 150 mg/day including 704 clinically evaluable patients.
An objective response was achieved by between 28.0% and 100% of treated patients with laBCC and 30.8% and 38.0% of those with mBCC, with weighted averages of 64.7% and 33.6%, respectively.
The weighted average for a complete response in the laBCC and mBCC patient groups was 31.1% and 3.9%, respectively, and the median duration of therapy in the two groups was 37.0 weeks and 52.7 weeks, respectively.
Pooled analysis of adverse effects associated with vismodegib in 803 participants of nine trials indicated that serious adverse events occurred in between 0% and 38.5% of patients, with a weighted average of 21.4%.
Side effects led to discontinuation in a weighted average of 28.2% of patients, prompting the authors to suggest that vismodegib be considered for delivery as a “pulse treatment”.
Muscle spasms, dysguesia, weight loss, fatigue and alopecia occurred in a weighted average of 66.4%, 57.3%, 33.4%, 20.1% and 61.1% of patients, respectively. In addition, new-onset Squamous cell carcinoma was reported in a weighted average of 1.3% of patients.
John Strasswimmer et al explain that comparison of vismodegib with the HPI sonidegib was not possible as there are too few trial data for pooled analysis, but write that “we suspect that response rates and adverse effect profiles are similar owing to class effect”.
The authors conclude: “Hedgehog pathway inhibitors are an effective, well-tolerated therapy for laBCC and mBCC and have great potential to improve quality of life for many patients who have limited treatment options.
“The clinical experiences of these newly [US Food and Drug Administration]-approved medications should be critically evaluated to ensure best practices for future use.”
Reference
Jacobsen AA, Aldahan AS, Hughes OB, et al. Hedgehog pathway inhibitor therapy for locally advanced and metastatic basal cell carcinoma. JAMA Dermatol 2016; Advance online publication 20 April. doi:10.1001/jamadermatol.2016.0780
miércoles, 21 de septiembre de 2016
GenesisCare enters Spanish Market
GenesisCare enters Spanish Market
11 July 2016
GenesisCare acquires Spanish private cancer service provider IMOncology
GenesisCare, the largest private provider of radiotherapy services in Australia and the UK, today announced the completion of the acquisition of the leading Spanish private cancer service provider, IMOncology.
As the leading provider in Spain, IMOncology operates 12 treatment centres in 5 regions including Madrid, Sevilla, Murcia, Alicante and Castilla la Mancha.The well-established healthcare network provides high quality radiotherapy services and medical oncology services for both privately insured patients and on behalf of the Spanish National Health Service.
With this acquisition GenesisCare will treat more than 26,000 cancer patients a year across Australia, UK and Spain.
Marian Isach, General Director of Operations for IMOncology, said “For 25 years, we have been committed to delivering personalised patient care while leading the way with new treatment techniques of radiotherapy. Our partnership with GenesisCare will allow us to share knowledge and skills to enable a stronger, coordinated approach to cancer care in Spain”.
Corporate General Director of IMOncology Pablo Jiménez-Herrera, added that he is looking forward to seeing the positive outcomes for patients, doctors, staff and partner hospitals.
“Investment in the latest technology and treatment techniques, along with training and education for staff, will help us to develop a more integrated cancer service. We are truly excited as we enter into the next stage of our development with GenesisCare in Spain,” Mr Jimenez-Herrera said.
GenesisCare Managing Director, Dan Collins, explained that by sharing knowledge and best practice the organisation will continue to improve cancer care for patients across the world.
“At GenesisCare we are always looking for ways to improve our service to patients. Collaborating with IMOncology will help us to achieve our shared vision to deliver high quality treatment to ensure that all patients receive the best care outcomes when they need it,” Mr Collins said.
The expansion by GenesisCare into Spain and Western Europe is a natural step for the organisation following on from the commencement of operations in the United Kingdom with its acquisition of Cancer Partners UK 12 months ago.
11 July 2016
GenesisCare acquires Spanish private cancer service provider IMOncology
GenesisCare, the largest private provider of radiotherapy services in Australia and the UK, today announced the completion of the acquisition of the leading Spanish private cancer service provider, IMOncology.
As the leading provider in Spain, IMOncology operates 12 treatment centres in 5 regions including Madrid, Sevilla, Murcia, Alicante and Castilla la Mancha.The well-established healthcare network provides high quality radiotherapy services and medical oncology services for both privately insured patients and on behalf of the Spanish National Health Service.
With this acquisition GenesisCare will treat more than 26,000 cancer patients a year across Australia, UK and Spain.
Marian Isach, General Director of Operations for IMOncology, said “For 25 years, we have been committed to delivering personalised patient care while leading the way with new treatment techniques of radiotherapy. Our partnership with GenesisCare will allow us to share knowledge and skills to enable a stronger, coordinated approach to cancer care in Spain”.
Corporate General Director of IMOncology Pablo Jiménez-Herrera, added that he is looking forward to seeing the positive outcomes for patients, doctors, staff and partner hospitals.
“Investment in the latest technology and treatment techniques, along with training and education for staff, will help us to develop a more integrated cancer service. We are truly excited as we enter into the next stage of our development with GenesisCare in Spain,” Mr Jimenez-Herrera said.
GenesisCare Managing Director, Dan Collins, explained that by sharing knowledge and best practice the organisation will continue to improve cancer care for patients across the world.
“At GenesisCare we are always looking for ways to improve our service to patients. Collaborating with IMOncology will help us to achieve our shared vision to deliver high quality treatment to ensure that all patients receive the best care outcomes when they need it,” Mr Collins said.
The expansion by GenesisCare into Spain and Western Europe is a natural step for the organisation following on from the commencement of operations in the United Kingdom with its acquisition of Cancer Partners UK 12 months ago.
GenesisCare: Leading Australian healthcare provider sets out ambitious expansion plans with new co-investors
Leading Australian healthcare provider sets out ambitious expansion plans with new co-investors
Sydney – GenesisCare Limited, a leading healthcare provider in Australia, is pleased to announce it has entered into agreements for a new investment Consortium to acquire between 50.01 percent and up to 74 percent of the business.
The Consortium comprises Hong Kong-based China Resources Group and Macquarie Capital. Macquarie Capital, the corporate advisory arm of Australian-headquartered financial institution Macquarie Group, is the minority member of the Consortium and China Resources Group’s financial adviser.
The Consortium will invest alongside existing doctor and management shareholders. Global Investment firm KKR & Co, which currently holds 45 percent of GenesisCare will sell its stake in the business to the Consortium.
“This is a strategic partnership designed to use Australian expertise and technology to improve healthcare in new markets, including China, and to do so from an Australian base. A majority of the Board and the management team will remain in place with company headquarters in Sydney,” GenesisCare Chairman, David Vaux said.
“Our day to day clinical independence, clinical management committees and organisational structure will continue as it does today,” the Chairman said.
GenesisCare Managing Director, Dan Collins said the company was continuing expansion plans for Western Europe following its recent entry into the UK and Spain.
“With the strategic capability and positioning of China Resources Group, GenesisCare will accelerate plans for Asia and in particular China. There is a significant appetite for our world class capabilities in cancer and cardiac care. GenesisCare will become part of the solution in how China and developing Asia solves quality and access challenges around essential patient care,” he said.
GenesisCare is Australia’s largest provider of cancer and cardiac services and also the largest provider of private cancer services in Spain and the United Kingdom. The organisation treats more than 2500 patients every day in more than 150 locations across three countries and employs more than 2000 committed medical professionals and management staff.
Ms. Kerry Zhang Deputy General Manager, Strategy Management at China Resources, said: “GenesisCare is an Australian success story. It has developed a world class model for cancer and cardiac care that we will help introduce to China and take around the world. We look forward to backing the GenesisCare leadership team, and supporting its international expansion.”
Cameron Brownjohn of Macquarie Capital said: “We are pleased to be working alongside China Resources in supporting GenesisCare as it pursues its plans to take Australian expertise to international markets.”
GenesisCare Managing Director, Dan Collins paid tribute to KKR whose partnership had fostered the company’s growth.
“For the past four years, KKR has been an active partner in Genesis Care’s domestic growth and international expansion. We are proud of what Genesis Care has accomplished, and are confident this strong foundation will support further opportunities for this rapidly globalizing Australian brand,” Edward Bostock, Director, KKR Australia, said.
GenesisCare and the Consortium said that the catalyst for these discussions came from the recently struck Free Trade Agreement between Australia and China. This transaction underlines the move to a service economy in China, and the export demand for Australian healthcare expertise.
The Board will constitute five existing members - with two independent directors, including the Chairman, two GenesisCare doctors (a cardiologist and oncologist) and the Managing Director. The Consortium will contribute four board members including one from Macquarie Capital.
The existing doctor leadership teams will remain in place. Existing management and doctors are expected to continue to own between 26-50 percent of the company upon transaction completion depending on their shareholder elections
The transaction is subject to a Shareholder vote and Foreign Investment Review Board approval.
Sydney – GenesisCare Limited, a leading healthcare provider in Australia, is pleased to announce it has entered into agreements for a new investment Consortium to acquire between 50.01 percent and up to 74 percent of the business.
The Consortium comprises Hong Kong-based China Resources Group and Macquarie Capital. Macquarie Capital, the corporate advisory arm of Australian-headquartered financial institution Macquarie Group, is the minority member of the Consortium and China Resources Group’s financial adviser.
The Consortium will invest alongside existing doctor and management shareholders. Global Investment firm KKR & Co, which currently holds 45 percent of GenesisCare will sell its stake in the business to the Consortium.
“This is a strategic partnership designed to use Australian expertise and technology to improve healthcare in new markets, including China, and to do so from an Australian base. A majority of the Board and the management team will remain in place with company headquarters in Sydney,” GenesisCare Chairman, David Vaux said.
“Our day to day clinical independence, clinical management committees and organisational structure will continue as it does today,” the Chairman said.
GenesisCare Managing Director, Dan Collins said the company was continuing expansion plans for Western Europe following its recent entry into the UK and Spain.
“With the strategic capability and positioning of China Resources Group, GenesisCare will accelerate plans for Asia and in particular China. There is a significant appetite for our world class capabilities in cancer and cardiac care. GenesisCare will become part of the solution in how China and developing Asia solves quality and access challenges around essential patient care,” he said.
GenesisCare is Australia’s largest provider of cancer and cardiac services and also the largest provider of private cancer services in Spain and the United Kingdom. The organisation treats more than 2500 patients every day in more than 150 locations across three countries and employs more than 2000 committed medical professionals and management staff.
Ms. Kerry Zhang Deputy General Manager, Strategy Management at China Resources, said: “GenesisCare is an Australian success story. It has developed a world class model for cancer and cardiac care that we will help introduce to China and take around the world. We look forward to backing the GenesisCare leadership team, and supporting its international expansion.”
Cameron Brownjohn of Macquarie Capital said: “We are pleased to be working alongside China Resources in supporting GenesisCare as it pursues its plans to take Australian expertise to international markets.”
GenesisCare Managing Director, Dan Collins paid tribute to KKR whose partnership had fostered the company’s growth.
“For the past four years, KKR has been an active partner in Genesis Care’s domestic growth and international expansion. We are proud of what Genesis Care has accomplished, and are confident this strong foundation will support further opportunities for this rapidly globalizing Australian brand,” Edward Bostock, Director, KKR Australia, said.
GenesisCare and the Consortium said that the catalyst for these discussions came from the recently struck Free Trade Agreement between Australia and China. This transaction underlines the move to a service economy in China, and the export demand for Australian healthcare expertise.
The Board will constitute five existing members - with two independent directors, including the Chairman, two GenesisCare doctors (a cardiologist and oncologist) and the Managing Director. The Consortium will contribute four board members including one from Macquarie Capital.
The existing doctor leadership teams will remain in place. Existing management and doctors are expected to continue to own between 26-50 percent of the company upon transaction completion depending on their shareholder elections
The transaction is subject to a Shareholder vote and Foreign Investment Review Board approval.
GenesisCare Australia, History
Although Dan had limited knowledge of health care at the time, he was an experienced business analyst and those skills allowed him to effectively research and assess the challenges, risks and opportunities in our struggling health system.
Passion turned to intrigue and a real determination as Dan discovered the same problems occurring right around Australia: patients not accessing care at all, different standards of care, doctors and patients unable to use known guidelines to make the right decisions, significant waste and duplication and a funding model that was about to break. How would our health system cope with burgeoning patient demand, funding pressures, rapidly changing technology and an ageing population?
To tackle this challenge, Dan ultimately focused on a few simple priorities which were to improve health care quality and access ensuring patients received the right care when they needed it through a more sustainable and better funded model. He strongly believed that a different operating model needed to be developed which fostered alignment between all of the key stakeholders - the patient and referrer, doctors, professionals and hospitals providing care and how care was funded.
In 2003 Dan approached Dr Geoff Holt who led HeartCare Partners in Brisbane, a practice of seven well-regarded cardiologists. At the time HeartCare Partners had led the way in terms of group practice, sub specialisation, expert training and a move towards electronic medical records. With a shared view of what was possible and a strong desire to effect change, Geoff, Dan and the HeartCare Partners '7' set about putting together the right strategy and plans. They agreed to bring together like-minded doctors in a network to expand access to care, to make a meaningful difference to care standards and share best practice.
With the vision and plans clear, Dan teamed up with a cornerstone investing partner to make it all possible. He approached the then listed healthcare company, DCA Group, led by CEO, David Vaux (the current GenesisCare Chairman). Plans were expanded to cover cancer care also with the broader vision now capturing the two largest disease burdens in our country – cancer and cardiovascular disease. Alongside Dan, DCA provided an initial $10 million investment to launch the HeartCare network in December 2004. The CancerCare network launch followed shortly after.
Ten years on in 2014, GenesisCare is now the largest provider of comprehensive cancer, cardiovascular and sleep treatments to patients throughout Australia. The group has made a profound positive impact for patient access and care standards around the country providing more than 300,000 cancer treatments and over 400,000 cardiovascular treatments in the last 12 months. This has been made possible by a wonderful team of medical professionals and over 1300 employees providing care at 102 locations. GenesisCare now leads or participates in more than 110 clinical trials, provides care on behalf of government and is one of the largest trainers and educators of medical professionals in Australia.
Today, the organisation has a simple patient focused formula, which underpins every decision:
To provide high quality care;
To patients and communities in need;
By delivering the benefits of a group.
GenesisCare raises the standard of care by providing better support to the people looking after patients. Through a unified network, GenesisCare fosters the sharing of best practice around technology, training, clinical practice, process and systems to facilitate integrated care delivery. In the future, our vision for sustainable care excellence will continue to evolve to meet the needs of the Australian people and beyond.
domingo, 18 de septiembre de 2016
The glycocalyx, or sugars that surround cells: A New Approach to Cancer Immunotherapy
Moving Away from Chemo: New Approach to Cancer Immunotherapy
September 7, 2016 | Written By: Jennifer Ellis
4 33 2039
Why isn’t our immune system able to fight off cancer? This is a tough question cancer researchers have long been working on, and we are getting closer to figuring it out. When treating cancer, doctors are looking to immunotherapy and other alternatives to help target actual tumors instead of attacking all rapidly dividing cells in a patient’s body with chemotherapy.
Immunotherapy uses the immune system to recognize and destroy specific tumors or spreading cancer cells. Many immunotherapies to date activate and strengthen the adaptive immune system, similar to how vaccines allow protection to specific diseases. While these treatments have had some success, they are slow to develop as each therapy is very specific to a unique and known protein.
Carolyn Bertozzi of Stanford University has recently introduced a new approach to immunotherapy, activating another arm of the immune system, the innate immune system. The innate immune system, or non-specific immune system, provides general defense from infection by identifying and removing foreign bodies. Bertozzi hypothesized that there must be a way to push the immune system to recognize cancer cells more frequently and in a more general manner, based not only on protein recognition but on the sugars fixed to the outside of the cells. The study is published online in the Proceedings of the National Academy of Sciences.
The Bertozzi lab studies the glycocalyx, or sugars that surround cells, and how these sugars interact with the immune system. Cancer cells tend to be overlooked by the immune system as normal healthy cells, allowing them to metastasize and proliferate uncontrolled. New thinking highlights sugars surrounding cancer cells as part of the problem.
Lymphocytes and cancer cell
“This is a whole new dimension to immune therapy,” Bertozzi says, “People in this field are starting to appreciate that there are many different nodes that you need to affect to get a more robust immune reaction against a tumor, and the glycocalyx appears to be one of those nodes.”
It has long been known that certain sugars and proteins aid in masking cancer cells from the immune system. Bertozzi wanted to find out specifically what role sugars play in helping cancer cells hide.
She discovered that if certain sugars are present on cancer cells, therapies are less likely to be effective, and that these sugars can act as a signal to the innate immune system to ignore the cells. Sialic acid is one type of sugar associated with spreading cancer cells. Researchers in the Netherlands showed that excessively high sialic acid expression in cancer cells can affect undetected tumor growth and initiation of metastasis.
By removing sialic acid from the cancer cell surface, Bertozzi was able to trigger the innate immune system. The team used the common cancer therapy Herceptin, an antibody that binds to the HER2 protein expressed on some breast cancer cells, flagging the cell for destruction by natural killer (NK) cells. Bertozzi attached a chemical “cleaver” to the Herceptin antibody to create an antibody-enzyme conjugate. Once the antibody bound to the HER2 protein, the cleaver could cut off any nearby sugars on the cell surface. This lack of sugars decreased the mask on the tumor cells, allowing the innate immune system to recognize and destroy the cells more frequently. Essentially, Bertozzi discovered that the less sugars around a cancer cell, the more activation she saw from the immune system to destroy cancer cells.
This new approach provides a boost to cancer treatments by enabling current therapies to work more effectively on a broader range of patients. Not only could this method be applied to HER2 proteins using Herceptin making it more successful when less HER2 is expressed, but also potentially applied to a variety of other expressed proteins and sugars. This study was done in cell culture, providing a solid foundation for additional testing and the creation of new cancer treatments in patients. The approach brings to light a new way of thinking about the complex relationship between the innate immune system and cancer cells, and opens the door to advancing cancer immunotherapy.
Sources: Stanford Report, PNAS, NCBI
Article Written By:Jennifer Ellis
September 7, 2016 | Written By: Jennifer Ellis
4 33 2039
Why isn’t our immune system able to fight off cancer? This is a tough question cancer researchers have long been working on, and we are getting closer to figuring it out. When treating cancer, doctors are looking to immunotherapy and other alternatives to help target actual tumors instead of attacking all rapidly dividing cells in a patient’s body with chemotherapy.
Immunotherapy uses the immune system to recognize and destroy specific tumors or spreading cancer cells. Many immunotherapies to date activate and strengthen the adaptive immune system, similar to how vaccines allow protection to specific diseases. While these treatments have had some success, they are slow to develop as each therapy is very specific to a unique and known protein.
Carolyn Bertozzi of Stanford University has recently introduced a new approach to immunotherapy, activating another arm of the immune system, the innate immune system. The innate immune system, or non-specific immune system, provides general defense from infection by identifying and removing foreign bodies. Bertozzi hypothesized that there must be a way to push the immune system to recognize cancer cells more frequently and in a more general manner, based not only on protein recognition but on the sugars fixed to the outside of the cells. The study is published online in the Proceedings of the National Academy of Sciences.
The Bertozzi lab studies the glycocalyx, or sugars that surround cells, and how these sugars interact with the immune system. Cancer cells tend to be overlooked by the immune system as normal healthy cells, allowing them to metastasize and proliferate uncontrolled. New thinking highlights sugars surrounding cancer cells as part of the problem.
Lymphocytes and cancer cell
“This is a whole new dimension to immune therapy,” Bertozzi says, “People in this field are starting to appreciate that there are many different nodes that you need to affect to get a more robust immune reaction against a tumor, and the glycocalyx appears to be one of those nodes.”
It has long been known that certain sugars and proteins aid in masking cancer cells from the immune system. Bertozzi wanted to find out specifically what role sugars play in helping cancer cells hide.
She discovered that if certain sugars are present on cancer cells, therapies are less likely to be effective, and that these sugars can act as a signal to the innate immune system to ignore the cells. Sialic acid is one type of sugar associated with spreading cancer cells. Researchers in the Netherlands showed that excessively high sialic acid expression in cancer cells can affect undetected tumor growth and initiation of metastasis.
By removing sialic acid from the cancer cell surface, Bertozzi was able to trigger the innate immune system. The team used the common cancer therapy Herceptin, an antibody that binds to the HER2 protein expressed on some breast cancer cells, flagging the cell for destruction by natural killer (NK) cells. Bertozzi attached a chemical “cleaver” to the Herceptin antibody to create an antibody-enzyme conjugate. Once the antibody bound to the HER2 protein, the cleaver could cut off any nearby sugars on the cell surface. This lack of sugars decreased the mask on the tumor cells, allowing the innate immune system to recognize and destroy the cells more frequently. Essentially, Bertozzi discovered that the less sugars around a cancer cell, the more activation she saw from the immune system to destroy cancer cells.
This new approach provides a boost to cancer treatments by enabling current therapies to work more effectively on a broader range of patients. Not only could this method be applied to HER2 proteins using Herceptin making it more successful when less HER2 is expressed, but also potentially applied to a variety of other expressed proteins and sugars. This study was done in cell culture, providing a solid foundation for additional testing and the creation of new cancer treatments in patients. The approach brings to light a new way of thinking about the complex relationship between the innate immune system and cancer cells, and opens the door to advancing cancer immunotherapy.
Sources: Stanford Report, PNAS, NCBI
Article Written By:Jennifer Ellis
sábado, 17 de septiembre de 2016
Obesity and Kidney cancer: Confirmed: Obesity Actually Improves Survival in This Cancer
Medscape Medical News > Oncology
Confirmed: Obesity Actually Improves Survival in This Cancer
Megan Brooks
September 14, 2016
New data support an obesity paradox in patients with metastatic kidney cancer treated with modern targeted therapy.
In two large and distinct datasets, high body mass index (BMI) was a prognostic factor for improved overall survival (OS) and progression-free survival (PFS) in patients with metastatic renal cell carcinoma (RCC), even after adjusting for known prognostic factors.
The fact that obese patients have better survival than counterparts with a lower BMI is considered paradoxical because overweight has been shown in multiple cancers to be a risk factor both for developing cancer and for worse outcomes.
"It is an interesting observation that obese patients may do better when they have stage IV disease. This builds on prior work and validates the findings in a new cohort," lead study author Toni K. Choueiri, MD, of Dana-Farber Cancer Institute/Brigham and Women's Hospital in Boston, Massachusetts, told Medscape Medical News.
Another expert who was asked for comment agreed that the evidence is building.
Thomas Olencki, DO, a kidney cancer specialist at the Ohio State University Comprehensive Cancer Center in Columbus, said everyone initially was "incredulous" about the apparent obesity paradox in RCC, but it now has "large patient numbers, reproducibility in different cohorts, and robust statistics, demonstrating this is a real effect."
This is a real effect.
Dr Thomas Olencki
There is a plausible mechanistic explanation behind the data, said Dr Choueiri.
"The biologic rationale may be explained by alterations in the FASN [fatty acid synthase] pathway. We are trying to see if there is any therapeutic opportunity," he said. "We want to go back to the lab and explore in animal models the implication of FASN on growth of RCC tumors in combination with established standard drugs."
Dr Choueiri and colleagues' findings were reported online September 6 in the Journal of Clinical Oncology.
They investigated the impact of BMI on OS and outcomes of targeted therapy in 1975 patients from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) and in an external validation cohort of 4657 patients treated for kidney cancer in clinical trials from 2003 to 2013.
In the IMDC cohort, median OS was 25.6 months (95% confidence interval [CI], 23.2 - 28.6) in patients with high BMI (≥25 kg/m2) compared with 17.1 months (95% CI, 15.5 - 18.5) in patients with low BMI (<25 kg/m2). The adjusted hazard ratio (HR) was 0.84 (95% CI, 0.73 - 0.95) The association of BMI with OS was evident in the intermediate- and poor-risk groups but not in the favorable group. Patients with high BMI also had longer time to treatment failure relative to their peers with low BMI in both first- and second-line treatment settings, after adjusting for prognostic factors. The results were similar in the validation cohort, with high BMI associated with improved OS (adjusted HR, 0.83; 95% CI, 0.74 - 0.93). Median OS was 23.4 months (95% CI, 21.9 - 25.3 months) with high BMI vs 14.5 months (95% CI, 13.8 - 15.9 months) with low BMI. There were also links between tumor FASN pathway activation (FASN gene expression and immunohistochemistry [IHC]) and BMI and survival. Among 61 patients with metastatic RCC in the Kidney Renal Clear Cell Carcinoma clinical TCGA consortium (cTCGA) cohort, FASN gene expression inversely correlated with BMI (P = .03), and high FASN expression was associated with worse OS (15.0 months vs 36.8 months with low FASN expression; P = .002). Among 146 patients in the IDMC cohort with metastatic RCC treated with targeted therapy, positive results on FASN staining, evident in 45 patients (31%), were more common in poor-risk (11 of 23, 48%) and intermediate-risk (20 of 59, 34%) groups compared with favorable-risk groups (5 of 30, 17%). When stratified by FASN IHC expression, OS was 27.5 months in FASN-negative patients vs 14.5 months in FASN-positive patients (HR, 1.71; 95% CI, 1.17 - 2.51; P = .005).
Clinically Relevant Now?
These observations suggest an "integral role" for tumor fatty acid metabolism in the prognosis of patients with mRCC and "lays the groundwork for future therapeutic interventions that target the FASN pathway," Dr Choueiri and colleagues conclude.
FASN is a key enzyme involved in neoplastic lipogenesis. Overexpression of FASN is common in many cancers and confers a survival growth advantage. FASN acts as a metabolic oncogene, having been associated with poor prognosis in several types of cancer, including kidney cancer. Its downregulation in overweight and obese mRCC patients in this analysis could explain why these individuals fared better than their normal-weight peers with increased FASN expression, Dr Choueiri and colleagues say.
It is still unclear why FASN may be downregulated in the setting of overweight/obesity, but the results provide a rationale for studies aimed at determining the effects of inhibiting FASN expression in RCC, regardless of BMI, the investigators say.
In an interview with Medscape Medical News, Ohio State's Dr Olencki agrees that the role of the FASN pathway in kidney cancer "has to be looked into further; clearly it is a possible therapeutic target."
Benjamin Gartrell, MD, medical oncologist at Montefiore Einstein Center for Cancer Care, New York City, told Medscape Medical News that the idea of an obesity paradox in RCC "has been around for a while, but this study provides more data to support it, and with a bigger group of patients. I suspect the difference is not necessarily the weight of the patient per se, but it's the cancer that is more likely to develop in an overweight patient tends to have a more indolent biology."
Dr Gartrell thinks the findings have clinical relevance. "Here at the Montefiore Einstein Center for Cancer Care, one of our priorities initially when we are meeting a patient is to try to give as much prognostic information as we can, and I think now we might consider incorporating the patient's weight to the prognostic information we provide to a patient."
The study was supported by the Dana-Farber/Harvard Cancer Center Kidney Cancer and the Kidney Cancer Foundation. Several authors have disclosed financial relationships with various pharmaceutical companies. A complete list can be found with the original article.
J Clin Oncol. Published online September 6, 2016. Abstract
Confirmed: Obesity Actually Improves Survival in This Cancer
Megan Brooks
September 14, 2016
New data support an obesity paradox in patients with metastatic kidney cancer treated with modern targeted therapy.
In two large and distinct datasets, high body mass index (BMI) was a prognostic factor for improved overall survival (OS) and progression-free survival (PFS) in patients with metastatic renal cell carcinoma (RCC), even after adjusting for known prognostic factors.
The fact that obese patients have better survival than counterparts with a lower BMI is considered paradoxical because overweight has been shown in multiple cancers to be a risk factor both for developing cancer and for worse outcomes.
"It is an interesting observation that obese patients may do better when they have stage IV disease. This builds on prior work and validates the findings in a new cohort," lead study author Toni K. Choueiri, MD, of Dana-Farber Cancer Institute/Brigham and Women's Hospital in Boston, Massachusetts, told Medscape Medical News.
Another expert who was asked for comment agreed that the evidence is building.
Thomas Olencki, DO, a kidney cancer specialist at the Ohio State University Comprehensive Cancer Center in Columbus, said everyone initially was "incredulous" about the apparent obesity paradox in RCC, but it now has "large patient numbers, reproducibility in different cohorts, and robust statistics, demonstrating this is a real effect."
This is a real effect.
Dr Thomas Olencki
There is a plausible mechanistic explanation behind the data, said Dr Choueiri.
"The biologic rationale may be explained by alterations in the FASN [fatty acid synthase] pathway. We are trying to see if there is any therapeutic opportunity," he said. "We want to go back to the lab and explore in animal models the implication of FASN on growth of RCC tumors in combination with established standard drugs."
Dr Choueiri and colleagues' findings were reported online September 6 in the Journal of Clinical Oncology.
They investigated the impact of BMI on OS and outcomes of targeted therapy in 1975 patients from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) and in an external validation cohort of 4657 patients treated for kidney cancer in clinical trials from 2003 to 2013.
In the IMDC cohort, median OS was 25.6 months (95% confidence interval [CI], 23.2 - 28.6) in patients with high BMI (≥25 kg/m2) compared with 17.1 months (95% CI, 15.5 - 18.5) in patients with low BMI (<25 kg/m2). The adjusted hazard ratio (HR) was 0.84 (95% CI, 0.73 - 0.95) The association of BMI with OS was evident in the intermediate- and poor-risk groups but not in the favorable group. Patients with high BMI also had longer time to treatment failure relative to their peers with low BMI in both first- and second-line treatment settings, after adjusting for prognostic factors. The results were similar in the validation cohort, with high BMI associated with improved OS (adjusted HR, 0.83; 95% CI, 0.74 - 0.93). Median OS was 23.4 months (95% CI, 21.9 - 25.3 months) with high BMI vs 14.5 months (95% CI, 13.8 - 15.9 months) with low BMI. There were also links between tumor FASN pathway activation (FASN gene expression and immunohistochemistry [IHC]) and BMI and survival. Among 61 patients with metastatic RCC in the Kidney Renal Clear Cell Carcinoma clinical TCGA consortium (cTCGA) cohort, FASN gene expression inversely correlated with BMI (P = .03), and high FASN expression was associated with worse OS (15.0 months vs 36.8 months with low FASN expression; P = .002). Among 146 patients in the IDMC cohort with metastatic RCC treated with targeted therapy, positive results on FASN staining, evident in 45 patients (31%), were more common in poor-risk (11 of 23, 48%) and intermediate-risk (20 of 59, 34%) groups compared with favorable-risk groups (5 of 30, 17%). When stratified by FASN IHC expression, OS was 27.5 months in FASN-negative patients vs 14.5 months in FASN-positive patients (HR, 1.71; 95% CI, 1.17 - 2.51; P = .005).
Clinically Relevant Now?
These observations suggest an "integral role" for tumor fatty acid metabolism in the prognosis of patients with mRCC and "lays the groundwork for future therapeutic interventions that target the FASN pathway," Dr Choueiri and colleagues conclude.
FASN is a key enzyme involved in neoplastic lipogenesis. Overexpression of FASN is common in many cancers and confers a survival growth advantage. FASN acts as a metabolic oncogene, having been associated with poor prognosis in several types of cancer, including kidney cancer. Its downregulation in overweight and obese mRCC patients in this analysis could explain why these individuals fared better than their normal-weight peers with increased FASN expression, Dr Choueiri and colleagues say.
It is still unclear why FASN may be downregulated in the setting of overweight/obesity, but the results provide a rationale for studies aimed at determining the effects of inhibiting FASN expression in RCC, regardless of BMI, the investigators say.
In an interview with Medscape Medical News, Ohio State's Dr Olencki agrees that the role of the FASN pathway in kidney cancer "has to be looked into further; clearly it is a possible therapeutic target."
Benjamin Gartrell, MD, medical oncologist at Montefiore Einstein Center for Cancer Care, New York City, told Medscape Medical News that the idea of an obesity paradox in RCC "has been around for a while, but this study provides more data to support it, and with a bigger group of patients. I suspect the difference is not necessarily the weight of the patient per se, but it's the cancer that is more likely to develop in an overweight patient tends to have a more indolent biology."
Dr Gartrell thinks the findings have clinical relevance. "Here at the Montefiore Einstein Center for Cancer Care, one of our priorities initially when we are meeting a patient is to try to give as much prognostic information as we can, and I think now we might consider incorporating the patient's weight to the prognostic information we provide to a patient."
The study was supported by the Dana-Farber/Harvard Cancer Center Kidney Cancer and the Kidney Cancer Foundation. Several authors have disclosed financial relationships with various pharmaceutical companies. A complete list can be found with the original article.
J Clin Oncol. Published online September 6, 2016. Abstract
domingo, 4 de septiembre de 2016
NSCLC: Similar Immunotherapy Trials, Different Results. Early Signals From PD-1 Checkpoint Inhibitors in First-Line NSCLC
Similar Immunotherapy Trials, Different Results: Early Signals From PD-1 Checkpoint Inhibitors in First-Line NSCLC
H. Jack West, MD
Disclosures|August 25, 2016
The evolution of the role of immunotherapy for patients with non-small cell lung cancer (NSCLC), as well as many other cancers, has been rapid and dramatic. The PD-1 checkpoint inhibitor nivolumab was approved by the US Food and Drug Administration (FDA) as a second-line therapy on the basis of a demonstrated significant survival benefit compared with docetaxel in PD-L1 expression–unselected patients, first in those with squamous NSCLC[1] and later in patients with nonsquamous NSCLC histology.[2] Pembrolizumab, with the same mechanism of action, was also FDA approved in late 2015 following previous treatment for patients with advanced squamous or nonsquamous NSCLC. But the focus with pembrolizumab has been on patients with significant PD-L1 expression[3]; in contrast to the "PD-L1 agnostic" approval of nivolumab, approval of pembrolizumab was specifically for patients who were positive on testing with the 22C3 antibody as a companion diagnostic test,[4] which defines positivity using a 50% expression level as a cutoff. This high bar is present in less than 30% of patients, making it restrictive but enriching for those patients most likely to benefit from immunotherapy. Though improved survival with pembrolizumab compared with second-line docetaxel has also been demonstrated in a more liberally defined population with any degree of PD-L1 expression,[5] this has yet to translate into a change in indication for advanced NSCLC.
The fate of these two remarkably similar agents has been largely dictated by their differing indications.
The fate of these two remarkably similar agents has been largely dictated by their differing indications, which are the result of strategic decisions by the companies that developed them. Despite evidence that the efficacy of nivolumab as second-line therapy for at least nonsquamous NSCLC patients is correlated with PD-L1 expression (as measured by a different antibody and different cutoffs from those used for pembrolizumab),[2] the survival benefit of nivolumab over docetaxel in the broad range of unselected patients was sufficient to justify approval and use without prospective PD-L1 testing. This has led to treatment patterns in the United States that have overwhelmingly favored the use of second-line nivolumab without advance testing for PD-L1, in contrast with the requirement to test for PD-L1 using a relatively high threshold level of expression in order to have the opportunity to treat with pembrolizumab. Treating without a required threshold of PD-L1 expression led to a clear win in round 1 for nivolumab.
The promise of dramatic and prolonged responses to immune checkpoint inhibitors with little or no significant toxicity logically leads to extensive testing in the first-line setting. Accordingly, scores of trials with multiple PD-1 or PD-L1 checkpoint inhibitors integrated into the first-line setting have been conducted and are continuing enrollment.The array of studies varies across several critical variables:
Scores of trials with multiple PD-1 or PD-L1 checkpoint inhibitors integrated into the first-line setting have been conducted and are continuing enrollment.
Patient selection: All patients or limited by squamous or nonsquamous histology, and/or restricted by PD-L1 status?
Which PD-1 or PD-L1 checkpoint inhibitor is studied?
Is the PD-1 or PD-L1 inhibitor administered as monotherapy or as part of a combination (with standard first-line therapy or another immunotherapy, such as a CTLA-4 inhibitor), or both?
Is treatment with the immunotherapy for a limited or indefinite duration?
For patients assigned to the control arm, is crossover to immunotherapy permitted?
For the clear majority of these trials, progression-free survival (PFS) has been the primary endpoint, largely out of concern that subsequent therapies will eliminate the ability to discern the benefit of first-line treatment. However, response rate (RR) and PFS are potentially confounded by the long-recognized difficulty of interpreting response to immunotherapy, making it difficult or impossible to define an optimal primary endpoint for first-line treatment.
In this setting of so many uncertainties, the preliminary results of two critically important, seemingly similar first-line trials have become available, at least in the form of official press releases, with very discordant results. The KEYNOTE-024 trial randomly assigned 305 treatment-naive advanced NSCLC with PD-L1 expression of >50% (approximately 28% of all patients) to either any of several platinum-based doublets or pembrolizumab at a new, fixed dose of 200 mg IV every 3 weeks. The press release noted that recipients of first-line pembrolizumab demonstrated not only a significantly longer PFS but also a significantly improved overall survival (OS), despite the fact that patients assigned to initial chemotherapy could cross over to pembrolizumab upon progression.[6] Though we have yet to view the actual data, this report indicates that pembrolizumab is not only highly effective for this subset of patients, but also that it is most beneficial when administered as early as possible. At the same time, this subset is the minority of patients most likely to benefit from an immune checkpoint inhibitor, so it would be a mistake to presume that these results can be generalized to a less stringently selected patient population.
Is there reason to suspect that there are clinically significant differences among the many checkpoint inhibitors being tested?
This last point was underscored by the sobering press release describing the negative results of the CheckMate-026 trial,[7] which randomly assigned 541 advanced NSCLC patients with a less strict PD-L1 cutoff point of 5% with a different antibody (corresponding to about 40%-45% of patients being included) to one of multiple platinum-based doublet chemotherapy regimens or nivolumab at 2 mg/kg IV every 2 weeks. The study failed to demonstrate a significant improvement in PFS, and though no information was provided about OS, we might infer that a positive result was probably not withheld; companies rarely sit on good news.
We await the presentation of the data from these trials, but in the meantime, we should ask ourselves how to make sense of these similar trials producing such different outcomes. Is pembrolizumab, seemingly so similar in its efficacy and tolerability in the second line, a significantly better agent than nivolumab? Is there reason to suspect that there are clinically significant differences among the many checkpoint inhibitors being tested?
My explanation is that these agents are still remarkably similar in efficacy and that the marked difference in outcome is attributable to the critical importance of patient selection in the first-line setting, far more so than among previously treated patients. Even with only a minority of patients demonstrating a response to second-line nivolumab—approximately 20% in the studies of squamous[1] and nonsquamous NSCLC[2]—and many other patients diluting the very good outcome with nivolumab in that minority, nivolumab bested a weak opponent in second-line docetaxel. But considerably more active first-line doublet chemotherapy offers less opportunity to dilute the benefit seen in a minority. Whether the proportion of patients who benefit significantly more from PD-1 checkpoint inhibitor therapy is 20% or closer to the approximately 28% of patients "cherry-picked" for KEYNOTE-024, the selected but broader population eligible for CheckMate-026 diluted this subset of more immune-sensitive patients with too many patients who were not actually beneficiaries of immunotherapy. This approach undermined the benefits of immunotherapy that would likely also have been conferred by nivolumab in a more select subset of patients who met the eligibility criteria for the pembrolizumab trial.
Immunotherapy will transform the first-line landscape, but not by overturning standard therapy for most or all patients.
Of course, this remains only a hypothesis, especially without the data to review from these studies. As we continue to receive data on an ever-growing collection of trials featuring first-line immunotherapy, our understanding will continue to be refined, and we will need to integrate data on findings of combinations of PD-1 or PD-L1 checkpoint inhibitors with other immunotherapies, conventional chemotherapy, and targeted therapies. But even this first volley of press releases already confirms that immunotherapy will transform the first-line landscape, but not by overturning standard therapy for most or all patients.
H. Jack West, MD
Disclosures|August 25, 2016
The evolution of the role of immunotherapy for patients with non-small cell lung cancer (NSCLC), as well as many other cancers, has been rapid and dramatic. The PD-1 checkpoint inhibitor nivolumab was approved by the US Food and Drug Administration (FDA) as a second-line therapy on the basis of a demonstrated significant survival benefit compared with docetaxel in PD-L1 expression–unselected patients, first in those with squamous NSCLC[1] and later in patients with nonsquamous NSCLC histology.[2] Pembrolizumab, with the same mechanism of action, was also FDA approved in late 2015 following previous treatment for patients with advanced squamous or nonsquamous NSCLC. But the focus with pembrolizumab has been on patients with significant PD-L1 expression[3]; in contrast to the "PD-L1 agnostic" approval of nivolumab, approval of pembrolizumab was specifically for patients who were positive on testing with the 22C3 antibody as a companion diagnostic test,[4] which defines positivity using a 50% expression level as a cutoff. This high bar is present in less than 30% of patients, making it restrictive but enriching for those patients most likely to benefit from immunotherapy. Though improved survival with pembrolizumab compared with second-line docetaxel has also been demonstrated in a more liberally defined population with any degree of PD-L1 expression,[5] this has yet to translate into a change in indication for advanced NSCLC.
The fate of these two remarkably similar agents has been largely dictated by their differing indications.
The fate of these two remarkably similar agents has been largely dictated by their differing indications, which are the result of strategic decisions by the companies that developed them. Despite evidence that the efficacy of nivolumab as second-line therapy for at least nonsquamous NSCLC patients is correlated with PD-L1 expression (as measured by a different antibody and different cutoffs from those used for pembrolizumab),[2] the survival benefit of nivolumab over docetaxel in the broad range of unselected patients was sufficient to justify approval and use without prospective PD-L1 testing. This has led to treatment patterns in the United States that have overwhelmingly favored the use of second-line nivolumab without advance testing for PD-L1, in contrast with the requirement to test for PD-L1 using a relatively high threshold level of expression in order to have the opportunity to treat with pembrolizumab. Treating without a required threshold of PD-L1 expression led to a clear win in round 1 for nivolumab.
The promise of dramatic and prolonged responses to immune checkpoint inhibitors with little or no significant toxicity logically leads to extensive testing in the first-line setting. Accordingly, scores of trials with multiple PD-1 or PD-L1 checkpoint inhibitors integrated into the first-line setting have been conducted and are continuing enrollment.The array of studies varies across several critical variables:
Scores of trials with multiple PD-1 or PD-L1 checkpoint inhibitors integrated into the first-line setting have been conducted and are continuing enrollment.
Patient selection: All patients or limited by squamous or nonsquamous histology, and/or restricted by PD-L1 status?
Which PD-1 or PD-L1 checkpoint inhibitor is studied?
Is the PD-1 or PD-L1 inhibitor administered as monotherapy or as part of a combination (with standard first-line therapy or another immunotherapy, such as a CTLA-4 inhibitor), or both?
Is treatment with the immunotherapy for a limited or indefinite duration?
For patients assigned to the control arm, is crossover to immunotherapy permitted?
For the clear majority of these trials, progression-free survival (PFS) has been the primary endpoint, largely out of concern that subsequent therapies will eliminate the ability to discern the benefit of first-line treatment. However, response rate (RR) and PFS are potentially confounded by the long-recognized difficulty of interpreting response to immunotherapy, making it difficult or impossible to define an optimal primary endpoint for first-line treatment.
In this setting of so many uncertainties, the preliminary results of two critically important, seemingly similar first-line trials have become available, at least in the form of official press releases, with very discordant results. The KEYNOTE-024 trial randomly assigned 305 treatment-naive advanced NSCLC with PD-L1 expression of >50% (approximately 28% of all patients) to either any of several platinum-based doublets or pembrolizumab at a new, fixed dose of 200 mg IV every 3 weeks. The press release noted that recipients of first-line pembrolizumab demonstrated not only a significantly longer PFS but also a significantly improved overall survival (OS), despite the fact that patients assigned to initial chemotherapy could cross over to pembrolizumab upon progression.[6] Though we have yet to view the actual data, this report indicates that pembrolizumab is not only highly effective for this subset of patients, but also that it is most beneficial when administered as early as possible. At the same time, this subset is the minority of patients most likely to benefit from an immune checkpoint inhibitor, so it would be a mistake to presume that these results can be generalized to a less stringently selected patient population.
Is there reason to suspect that there are clinically significant differences among the many checkpoint inhibitors being tested?
This last point was underscored by the sobering press release describing the negative results of the CheckMate-026 trial,[7] which randomly assigned 541 advanced NSCLC patients with a less strict PD-L1 cutoff point of 5% with a different antibody (corresponding to about 40%-45% of patients being included) to one of multiple platinum-based doublet chemotherapy regimens or nivolumab at 2 mg/kg IV every 2 weeks. The study failed to demonstrate a significant improvement in PFS, and though no information was provided about OS, we might infer that a positive result was probably not withheld; companies rarely sit on good news.
We await the presentation of the data from these trials, but in the meantime, we should ask ourselves how to make sense of these similar trials producing such different outcomes. Is pembrolizumab, seemingly so similar in its efficacy and tolerability in the second line, a significantly better agent than nivolumab? Is there reason to suspect that there are clinically significant differences among the many checkpoint inhibitors being tested?
My explanation is that these agents are still remarkably similar in efficacy and that the marked difference in outcome is attributable to the critical importance of patient selection in the first-line setting, far more so than among previously treated patients. Even with only a minority of patients demonstrating a response to second-line nivolumab—approximately 20% in the studies of squamous[1] and nonsquamous NSCLC[2]—and many other patients diluting the very good outcome with nivolumab in that minority, nivolumab bested a weak opponent in second-line docetaxel. But considerably more active first-line doublet chemotherapy offers less opportunity to dilute the benefit seen in a minority. Whether the proportion of patients who benefit significantly more from PD-1 checkpoint inhibitor therapy is 20% or closer to the approximately 28% of patients "cherry-picked" for KEYNOTE-024, the selected but broader population eligible for CheckMate-026 diluted this subset of more immune-sensitive patients with too many patients who were not actually beneficiaries of immunotherapy. This approach undermined the benefits of immunotherapy that would likely also have been conferred by nivolumab in a more select subset of patients who met the eligibility criteria for the pembrolizumab trial.
Immunotherapy will transform the first-line landscape, but not by overturning standard therapy for most or all patients.
Of course, this remains only a hypothesis, especially without the data to review from these studies. As we continue to receive data on an ever-growing collection of trials featuring first-line immunotherapy, our understanding will continue to be refined, and we will need to integrate data on findings of combinations of PD-1 or PD-L1 checkpoint inhibitors with other immunotherapies, conventional chemotherapy, and targeted therapies. But even this first volley of press releases already confirms that immunotherapy will transform the first-line landscape, but not by overturning standard therapy for most or all patients.
Ovarian Cancer: ASCO & SGO Neoadjuvant Chemo Now a Standard for Ovarian Cancer
ASCO & SGO: Neoadjuvant Chemo Now a Standard for Ovarian Cancer
Maurie Markman, MD
Disclosures | August 30, 2016
Hello. I'm Dr Maurie Markman from Cancer Treatment Centers of America in Philadelphia. I want to briefly discuss a very important paper, a position statement from the American Society of Clinical Oncology and the Society of Gynecologic Oncology, directly addressing the question of neoadjuvant chemotherapy for newly diagnosed advanced ovarian cancer.
This position paper and the data supporting it were just published in the Journal of Clinical Oncology.[1] There's been considerable debate in the gynecologic cancer community regarding the potential clinical utility for neoadjuvant chemotherapy followed by surgery versus primary surgery followed by chemotherapy in the management of advanced ovarian cancer.
The standard teaching, certainly in the gynecologic oncology community in the United States, is that the first effort should be an attempt at optimal surgical cytoreduction, traditionally described as no tumor mass more than 1 cm maximal diameter. Increasingly, this statement is made based upon quite reasonable data, but not from randomized control trials, where the goal should be to leave the patient with no gross residual disease at the end of surgery.
That has been the standard approach—surgery followed by chemotherapy. But there are now several phase 3 randomized trials that have demonstrated essentially equivalent progression-free survival and overall survival with reduced morbidity associated with the use of neoadjuvant chemotherapy versus primary surgical cytoreduction in a setting with quite advanced disease in the peritoneal cavity, when the initial therapy is contemplated.
Of course, this is somewhat of a subjective determination based upon not only the performance status of the patient and the extent of disease, but also on the surgical skills and surgical experience of the individual surgeon, as well as the hospital where the operation is going to be contemplated.
This position statement of the American Society of Clinical Oncology and the Society of Gynecologic Oncology clearly states that use of neoadjuvant chemotherapy followed by surgery is an acceptable therapeutic option based upon the available evidence in a setting where the surgeon and the surgical team do not feel that there is a high probability that the surgery can be performed resulting in that optimal surgical cytoreduction. And in that setting, admittedly, it's somewhat of a subjective determination based upon the skills and the knowledge of that gynecologic oncology surgical team. A very acceptable—in fact, perhaps you might strongly argue, preferable—option would be chemotherapy first followed by surgery where appropriate.
This is an important development, an important position statement from these two outstanding oncology groups regarding management of ovarian cancer. I would encourage anyone with an interest in the management of ovarian cancer to read this important paper, which just appeared in the Journal of Clinical Oncology. I thank you for your attention.
Maurie Markman, MD
Disclosures | August 30, 2016
Hello. I'm Dr Maurie Markman from Cancer Treatment Centers of America in Philadelphia. I want to briefly discuss a very important paper, a position statement from the American Society of Clinical Oncology and the Society of Gynecologic Oncology, directly addressing the question of neoadjuvant chemotherapy for newly diagnosed advanced ovarian cancer.
This position paper and the data supporting it were just published in the Journal of Clinical Oncology.[1] There's been considerable debate in the gynecologic cancer community regarding the potential clinical utility for neoadjuvant chemotherapy followed by surgery versus primary surgery followed by chemotherapy in the management of advanced ovarian cancer.
The standard teaching, certainly in the gynecologic oncology community in the United States, is that the first effort should be an attempt at optimal surgical cytoreduction, traditionally described as no tumor mass more than 1 cm maximal diameter. Increasingly, this statement is made based upon quite reasonable data, but not from randomized control trials, where the goal should be to leave the patient with no gross residual disease at the end of surgery.
That has been the standard approach—surgery followed by chemotherapy. But there are now several phase 3 randomized trials that have demonstrated essentially equivalent progression-free survival and overall survival with reduced morbidity associated with the use of neoadjuvant chemotherapy versus primary surgical cytoreduction in a setting with quite advanced disease in the peritoneal cavity, when the initial therapy is contemplated.
Of course, this is somewhat of a subjective determination based upon not only the performance status of the patient and the extent of disease, but also on the surgical skills and surgical experience of the individual surgeon, as well as the hospital where the operation is going to be contemplated.
This position statement of the American Society of Clinical Oncology and the Society of Gynecologic Oncology clearly states that use of neoadjuvant chemotherapy followed by surgery is an acceptable therapeutic option based upon the available evidence in a setting where the surgeon and the surgical team do not feel that there is a high probability that the surgery can be performed resulting in that optimal surgical cytoreduction. And in that setting, admittedly, it's somewhat of a subjective determination based upon the skills and the knowledge of that gynecologic oncology surgical team. A very acceptable—in fact, perhaps you might strongly argue, preferable—option would be chemotherapy first followed by surgery where appropriate.
This is an important development, an important position statement from these two outstanding oncology groups regarding management of ovarian cancer. I would encourage anyone with an interest in the management of ovarian cancer to read this important paper, which just appeared in the Journal of Clinical Oncology. I thank you for your attention.
viernes, 2 de septiembre de 2016
Aromatase-Inhibitors: Extending Aromatase-Inhibitor Adjuvant Therapy to 10 Years
Original Article
Extending Aromatase-Inhibitor Adjuvant Therapy to 10 Years
Paul E. Goss, M.D., Ph.D., James N. Ingle, M.D., Kathleen I. Pritchard, M.D., Nicholas J. Robert, M.D., Hyman Muss, M.D., Julie Gralow, M.D., Karen Gelmon, M.D., Tim Whelan, B.M., B.Ch., Kathrin Strasser-Weippl, M.D., Sheldon Rubin, M.D., Keren Sturtz, M.D., Antonio C. Wolff, M.D., Eric Winer, M.D., Clifford Hudis, M.D., Alison Stopeck, M.D., J. Thaddeus Beck, M.D., Judith S. Kaur, M.D., Kate Whelan, M.Sc., Dongsheng Tu, Ph.D., and Wendy R. Parulekar, M.D.
N Engl J Med 2016; 375:209-219July 21, 2016DOI: 10.1056/NEJMoa1604700
Background
Treatment with an aromatase inhibitor for 5 years as up-front monotherapy or after tamoxifen therapy is the treatment of choice for hormone-receptor–positive early breast cancer in postmenopausal women. Extending treatment with an aromatase inhibitor to 10 years may further reduce the risk of breast-cancer recurrence.
Methods
We conducted a double-blind, placebo-controlled trial to assess the effect of the extended use of letrozole for an additional 5 years. Our primary end point was disease-free survival.
Results
We enrolled 1918 women. After a median follow-up of 6.3 years, there were 165 events involving disease recurrence or the occurrence of contralateral breast cancer (67 with letrozole and 98 with placebo) and 200 deaths (100 in each group). The 5-year disease-free survival rate was 95% (95% confidence interval [CI], 93 to 96) with letrozole and 91% (95% CI; 89 to 93) with placebo (hazard ratio for disease recurrence or the occurrence of contralateral breast cancer, 0.66; P=0.01 by a two-sided log-rank test stratified according to nodal status, prior adjuvant chemotherapy, the interval from the last dose of aromatase-inhibitor therapy, and the duration of treatment with tamoxifen). The rate of 5-year overall survival was 93% (95% CI, 92 to 95) with letrozole and 94% (95% CI, 92 to 95) with placebo (hazard ratio, 0.97; P=0.83). The annual incidence rate of contralateral breast cancer in the letrozole group was 0.21% (95% CI, 0.10 to 0.32), and the rate in the placebo group was 0.49% (95% CI, 0.32 to 0.67) (hazard ratio, 0.42; P=0.007). Bone-related toxic effects occurred more frequently among patients receiving letrozole than among those receiving placebo, including a higher incidence of bone pain, bone fractures, and new-onset osteoporosis. No significant differences between letrozole and placebo were observed in scores on most subscales measuring quality of life.
Conclusions
The extension of treatment with an adjuvant aromatase inhibitor to 10 years resulted in significantly higher rates of disease-free survival and a lower incidence of contralateral breast cancer than those with placebo, but the rate of overall survival was not higher with the aromatase inhibitor than with placebo. (Funded by the Canadian Cancer Society and others; ClinicalTrials.gov numbers, NCT00003140 and NCT00754845.)
Supported by grants from the Canadian Cancer Society Research Institute (021039 and 015469), the National Cancer Institute (CA180888, CA189953, CA180828, CA13612, CA37981, CA077202, CA180863, CA67753, CA189805 [to Dr. Sturtz], CA16116, CA180802 [to Dr. Wolff], CA16116, and CA180802 [to Dr. Robert]), the Canadian Cancer Trials Group (CA077202 and CA180863), the ECOG-ACRIN Cancer Research Group (CA180820 and CA21115), and Novartis Pharmaceuticals. Dr. Goss was funded in part by the Avon Foundation.
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
Dr. Pritchard reports receiving fees for serving on advisory boards from AstraZeneca, Pfizer, Roche, Amgen, Novartis, GlaxoSmithKline and Eisai, consulting fees from Pfizer and Novartis, and lecture fees from Novartis; Dr. Muss, serving as an uncompensated consultant and advisor to Pfizer and HarborPath and serving on the board of directors of HarborPath; Dr. Gralow, serving on data safety and monitoring committees for Novartis and Roche-Genentech and on a steering committee for Roche-Genentech; Dr. Whelan, receiving fees for serving on an advisory board from Genomic Health and fees for testing reagents from NanoString; Dr. Winer, receiving grant support through his institution from Novartis; Dr. Hudis, receiving consulting fees and fees for serving on advisory boards from Novartis, Pfizer, and AstraZeneca; and Dr. Stopeck, receiving consulting fees from Amgen, Genentech, and BioMarin and honoraria from Amgen and serving on a data safety and monitoring committee for Pfizer and a steering committee for Sandoz. No other potential conflict of interest relevant to this article was reported.
This article was published on June 5, 2016, and last updated on June 28, 2016, at NEJM.org.
We thank Jessica St. Louis for her administrative support in the preparation and submission of an earlier version of this manuscript.
Extending Aromatase-Inhibitor Adjuvant Therapy to 10 Years
Paul E. Goss, M.D., Ph.D., James N. Ingle, M.D., Kathleen I. Pritchard, M.D., Nicholas J. Robert, M.D., Hyman Muss, M.D., Julie Gralow, M.D., Karen Gelmon, M.D., Tim Whelan, B.M., B.Ch., Kathrin Strasser-Weippl, M.D., Sheldon Rubin, M.D., Keren Sturtz, M.D., Antonio C. Wolff, M.D., Eric Winer, M.D., Clifford Hudis, M.D., Alison Stopeck, M.D., J. Thaddeus Beck, M.D., Judith S. Kaur, M.D., Kate Whelan, M.Sc., Dongsheng Tu, Ph.D., and Wendy R. Parulekar, M.D.
N Engl J Med 2016; 375:209-219July 21, 2016DOI: 10.1056/NEJMoa1604700
Background
Treatment with an aromatase inhibitor for 5 years as up-front monotherapy or after tamoxifen therapy is the treatment of choice for hormone-receptor–positive early breast cancer in postmenopausal women. Extending treatment with an aromatase inhibitor to 10 years may further reduce the risk of breast-cancer recurrence.
Methods
We conducted a double-blind, placebo-controlled trial to assess the effect of the extended use of letrozole for an additional 5 years. Our primary end point was disease-free survival.
Results
We enrolled 1918 women. After a median follow-up of 6.3 years, there were 165 events involving disease recurrence or the occurrence of contralateral breast cancer (67 with letrozole and 98 with placebo) and 200 deaths (100 in each group). The 5-year disease-free survival rate was 95% (95% confidence interval [CI], 93 to 96) with letrozole and 91% (95% CI; 89 to 93) with placebo (hazard ratio for disease recurrence or the occurrence of contralateral breast cancer, 0.66; P=0.01 by a two-sided log-rank test stratified according to nodal status, prior adjuvant chemotherapy, the interval from the last dose of aromatase-inhibitor therapy, and the duration of treatment with tamoxifen). The rate of 5-year overall survival was 93% (95% CI, 92 to 95) with letrozole and 94% (95% CI, 92 to 95) with placebo (hazard ratio, 0.97; P=0.83). The annual incidence rate of contralateral breast cancer in the letrozole group was 0.21% (95% CI, 0.10 to 0.32), and the rate in the placebo group was 0.49% (95% CI, 0.32 to 0.67) (hazard ratio, 0.42; P=0.007). Bone-related toxic effects occurred more frequently among patients receiving letrozole than among those receiving placebo, including a higher incidence of bone pain, bone fractures, and new-onset osteoporosis. No significant differences between letrozole and placebo were observed in scores on most subscales measuring quality of life.
Conclusions
The extension of treatment with an adjuvant aromatase inhibitor to 10 years resulted in significantly higher rates of disease-free survival and a lower incidence of contralateral breast cancer than those with placebo, but the rate of overall survival was not higher with the aromatase inhibitor than with placebo. (Funded by the Canadian Cancer Society and others; ClinicalTrials.gov numbers, NCT00003140 and NCT00754845.)
Supported by grants from the Canadian Cancer Society Research Institute (021039 and 015469), the National Cancer Institute (CA180888, CA189953, CA180828, CA13612, CA37981, CA077202, CA180863, CA67753, CA189805 [to Dr. Sturtz], CA16116, CA180802 [to Dr. Wolff], CA16116, and CA180802 [to Dr. Robert]), the Canadian Cancer Trials Group (CA077202 and CA180863), the ECOG-ACRIN Cancer Research Group (CA180820 and CA21115), and Novartis Pharmaceuticals. Dr. Goss was funded in part by the Avon Foundation.
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
Dr. Pritchard reports receiving fees for serving on advisory boards from AstraZeneca, Pfizer, Roche, Amgen, Novartis, GlaxoSmithKline and Eisai, consulting fees from Pfizer and Novartis, and lecture fees from Novartis; Dr. Muss, serving as an uncompensated consultant and advisor to Pfizer and HarborPath and serving on the board of directors of HarborPath; Dr. Gralow, serving on data safety and monitoring committees for Novartis and Roche-Genentech and on a steering committee for Roche-Genentech; Dr. Whelan, receiving fees for serving on an advisory board from Genomic Health and fees for testing reagents from NanoString; Dr. Winer, receiving grant support through his institution from Novartis; Dr. Hudis, receiving consulting fees and fees for serving on advisory boards from Novartis, Pfizer, and AstraZeneca; and Dr. Stopeck, receiving consulting fees from Amgen, Genentech, and BioMarin and honoraria from Amgen and serving on a data safety and monitoring committee for Pfizer and a steering committee for Sandoz. No other potential conflict of interest relevant to this article was reported.
This article was published on June 5, 2016, and last updated on June 28, 2016, at NEJM.org.
We thank Jessica St. Louis for her administrative support in the preparation and submission of an earlier version of this manuscript.
Metastatic Renal-Cell Carcinoma: Active Surveillance Feasible For Select Metastatic Renal-Cell Carcinoma Patients
Active Surveillance Feasible For Select Metastatic Renal-Cell Carcinoma Patients
Regular imaging may allow some renal-cell carcinoma patients with asymptomatic metastases to delay initiation of systemic treatment
Date: 04 Aug 2016
Author: By Lynda Williams, Senior medwireNews Reporter
Topic: Renal Cell Cancer
medwireNews: Active surveillance may be an option for asymptomatic patients with metastatic renal-cell carcinoma, suggest study findings published in The Lancet Oncology that indicate systemic therapy may be safely delayed in carefully selected cases.
The phase II trial performed at five hospitals in the USA, Spain and the UK monitored treatment-naive patients using computed tomography scans of the chest, abdomen and pelvis at baseline, every 3 months for the first year, every 4 months for the second year and at 6-month intervals thereafter.
In all, 48 of the 52 patients who were enrolled in the study were followed up for a median of 38.1 months. Active surveillance continued until the patient and physician chose to initiate systemic chemotherapy, which occurred after a median of 14.9 months.
RECIST-defined progression was reported in 90% of the patients after a median of 9.4 months, with 37 patients beginning systemic therapy and six continuing with surveillance for a further 15.8 months.
Symptomatic disease occurred in just two patients during surveillance, both of whom developed new sites of central nervous system metastases, prompting the authors to suggest routine neurological imaging during surveillance.
Exploratory analysis gave a median 12-month progression-free survival (PFS) rate of 41%, with 22%, 17% and 11% of patients still free from progression at 18, 24 and 36 months, respectively. Median overall survival from the start of surveillance was estimated to be 44.5 months.
Multivariate analysis showed that length of surveillance was significantly and independently predicted by number of involved organs and the number of International Metastatic Database Consortium (IMDC) risk factors.
Indeed, patients could be divided into two prognostic groups, such that the 60% of patients with up to two affected organs and no more than one IMDC risk factor achieved a significantly longer median surveillance time than the remaining patients with more affected organs and IMDC risk factors, at 22.2 versus 8.4 months.
“The present data should be interpreted in light of other therapeutic options in this disease”, write Brian Rini, from the Cleveland Clinic Taussig Cancer Institute in Ohio, USA, and co-investigators.
They say that their study patients had an “identical” 3-year PFS rate to that achieved in a trial of high-dose interleukin-2 and comparable clinical outcomes to a phase III trial comparing sunitinib versus pazopanib in patients with good- and intermediate-risk disease, albeit “with the important caveat that patients enrolled on our trial were highly selected and no direct comparison can be drawn for long-term survival.”
The authors conclude: “Taken together with published retrospective data, our findings show that select patients with metastatic renal-cell carcinoma can have prolonged time to cancer progression with surveillance prior to initiating systemic therapy.
“Additional experience is necessary to understand the risks and benefits of this approach.”
The author of an accompanying comment agrees: “This paper provides guidance to both medical and surgical oncologists who, when faced with a newly diagnosed patient with metastatic renal-cell carcinoma who has good performance status and limited metastatic disease, can offer a period of close surveillance with the potential for prolonged survival before disease progression and the initiation of systemic therapies.”
Paul Russo, from Memorial Sloan Kettering Cancer Center in New York, USA, concludes: “There is no evidence from this study that such a period of close surveillance jeopardises the patient’s safety or survival.”
References
Rini BI, Dorff TB, Rodriguez CS, et al. Active surveillance in metastatic renal-cell carcinoma: a propsective, phase 2 trial. Lancet Oncol 2016; Advance online publication 3 August. DOI: http://dx.doi.org/10.1016/S1470-2045(16)30196-6
Russo P. Delayed systemic treatment in metastatic renal-cell carcinoma. Lancet Oncol 2016; Advance online publication 3 August. DOI: http://dx.doi.org/10.1016/S1470-2045(16)30247-9
Advanced NSCLC: Reduced-Dose, MTD Erlotinib Outcomes Comparable
Reduced-Dose, MTD Erlotinib Outcomes Comparable In Advanced NSCLC
Non-small-cell lung cancer patients may derive survival benefit from erlotinib given below the maximum tolerated dose
Date: 17 Aug 2016
Author: Lynda Williams, Senior medwireNews Reporter
Topic: Anti-Cancer Agents & Biologic Therapy / Non-Small-Cell Lung Cancer, Metastatic
medwireNews: Erlotinib therapy is effective at prolonging progression-free survival (PFS) in non-small-cell lung cancer (NSCLC) patients when given below the maximum tolerated dose (MTD), say researchers who believe reduced-dose treatment may be feasible for individuals unable to tolerate the standard regimen.
The team reviewed the outcome of 198 patients with advanced NSCLC testing positive for Epidermal growth factor receptor (EGFR) L858R mutations or Exon 19 deletions who received erlotinib therapy, 16% of whose treatment was initiated on a reduced-dose.
Patients who received the reduced dose, defined as 100 mg/day or lower, were older and had a poorer performance status than those given the MTD of 150 mg/day.
But PFS did not significantly differ between the reduced-dose and MTD patient groups, at a median of 9.6 versus 11.4 months, say Geoffrey Oxnard, from Dana-Farber Cancer Institute in Boston, Massachusetts, USA, and co-authors in Cancer.
And although there was a trend towards a higher rate of central nervous system progression in patients given the reduced dose versus the MTD, at 17.5% versus 7.8%, this did not reach significance.
The team notes that dose reductions were common and occurred early in the course of treatment; 49% of the 167 patients whose treatment was initiated at the MTD were using a reduced dose at time of progression and 80% of dose reductions occurred within 4 months.
When outcome was assessed by actual erlotinib dose being used at the 4-month checkpoint, median PFS did not significantly differ between patients who began treatment on the MTD but had a dose reduction, the patients who continued to use the MTD after 4 months and those who received a reduced erlotinib dose throughout, at 6.9, 9.8 and 8.9 months, respectively.
After a median follow-up of 24.2 months, 157 of the study participants had died, including 90% of those given reduced-dose erlotinib and 77% of the patients who began treatment on the MTD.
However, after adjusting for age, gender, brain metastases, performance status and other factors, initial erlotinib dose did not significantly predict overall survival.
“Although this study did not examine adverse effects at reduced doses, it has been demonstrated that lower doses of erlotinib lead to a decreased incidence of side effects such as diarrhea”, the researchers write. “Therefore, reduced-dose erlotinib is a reasonable alternative to the MTD that does not significantly compromise efficacy.”
Moreover, Geoffrey Oxnard et al believe that their results have “potential implications for the future development of targeted agents”, citing their literature review showing that 15 of the 30 nonhormonal, small-molecular or kinase inhibitors approved or granted breakthrough status by the US Food and Drug Administration were evaluated at the MTD or the maximum dose tested.
These agents became more likely to be developed at a dose below the MTD over time, an “evolving approach” which the researchers believe indicates there is “uncertainty regarding the efficacy of submaximal doses.”
“When the toxicities of MTD dosing are a concern, an investigation of small-molecule inhibitors at doses below the MTD is warranted”, they conclude, emphasizing that “[b]roadly, small-molecule inhibitors represent a class of therapeutics in which additional studies on the efficacy of lower doses are needed.”
References
Lampson BL, Nishino M, Dahlberg SE, et al. Activity of erlotinib when dosed below the maximum tolerated dose for EGFR-mutant lung cancer: Implications for targeted therapy development. Cancer 2016; Advance online publication 15 August. DOI: 10.1002/cncr.30270
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