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CAR T-cell therapy: Moving from cost to value
Chimeric antigen receptor (CAR) T-cell therapy has generated a great deal of excitement in recent months with the approval of Novartis’ Kymriah (tisagenlecleucel) for pediatric acute lymphoblastic leukemia and Kite Pharma’s Yescarta (axicabtagene ciloleucel) for relapsed/refractory large B-cell lymphoma in adults, and experts in the field foresee a wave of approvals for additional indications in the coming months.
“CAR T is coming unbelievably fast,” Richard Maziarz, MD, professor of medicine at Oregon Health and Science University, Portland, said in an interview.
In fact, a search of clinicaltrials.gov revealed 120 open CAR T-cell–based therapy trials for cancer and other conditions such as autoimmune diseases, he said.
Price tag pressure
During a plenary session on genetically modified cell therapies at the annual meeting of the Society for Immunotherapy of Cancer, experts and investigators provided a glimpse of what’s in store, including new targets and smarter targeting and combinations that incorporate CAR T-cell therapy to treat solid tumors.
The “list price” for tisagenlecleucel is $475,000, and the potential patient pool is in the hundreds. The price for axicabtagene ciloleucel is $373,000, with a potential market in the thousands. Taking this into account, the global CAR T market is estimated at about $72 million and is projected to expand to nearly $3.5 billion in the next decade, said Dr. Maziarz, who is also chair of the Value and Health Economics Interest Group of the American Society for Blood and Marrow Transplantation.
The market for adoptive cell therapy overall – including transplant, CAR T, natural killer cells, and cell vaccines – is projected by some individuals to be worth $30 billion by 2030, he added, noting, for the sake of comparison, that the total estimated U.S. expenditure for all cancer care in the United States in 2010 was $125 billion.
At the heart of the issue of cost is the matter of value, he said.
“You can talk about price, and you can talk about cost, but … what we want to do with our dollars is buy value – and quality and value are very hard to measure,” he said, noting that he expects public and governmental backlash, as was seen with prior high-cost treatments such as Sovaldi for hepatitis C and Glybera for lipoprotein lipase deficiency.
Value-based payment is a recurrent theme in medicine, and these treatments came under intense scrutiny for their high costs. Sovaldi, for example, costs approximately $90,000 for a treatment course. That sounds like a lot of money, but it cures the disease and can prevent long-term complications, Dr. Maziarz said. Still, it received a lot of negative press, and the backlash was severe.
“People do respond to price,” he said, noting that he predicts the same for CAR T-cell therapies.
The costs of CAR T-cell therapy, particularly when taking into consideration the costs that hospitals will incur given the lymphodepletion that patients experience and the after-care required, will likely exceed those of most stem cell transplants and could easily reach the $1 million-plus estimates, Helen Heslop, MD, professor of medicine and pediatrics and director of the Center for Cell and Gene Therapy at Baylor College of Medicine, Houston, said in an interview.
Aside from the research and development costs, these treatments also cost more to make than any others previously made, according to Carl H. June, MD, the Richard W. Vague Professor In Immunotherapy at the University of Pennsylvania, Philadelphia, and a pioneer in CAR T-cell research.
Dr. June predicted that costs will be forced down over time because of process improvements and competition. “What’s unknown is the time span on how long it will take,” he said in an interview.
Groups like the United Kingdom’s National Institute for Health and Care Excellence (NICE) are already looking at value-based approaches to providing CAR T-cell therapy, Dr. Heslop said.
“I think there will need to be a lot more comparative effectiveness analyses done,” she said. “I know my institution started to look at the cost in a child with ALL once they relapse, and when you look at all the downstream cost, even though [CAR T-cell therapy] sounds very expensive, as a one-time therapy versus much longer treatment, it may actually be value based,” she said.
When it comes to improving access, one of the approaches being studied is the use of universal cell banks as opposed to autologous cells for therapy. This “off-the-shelf” approach, much like the approach used in transfusion medicine, would allow for quicker availability of the cells to a greater number of patients, she said.
Dr. June who, along with Dr. Heslop, cochaired the SITC plenary session on genetically modified cell therapy, agreed, saying that if this approach works with T cells, it would radically change the CAR T landscape in terms of availability and, perhaps – eventually – cost.
Preliminary results from phase I studies (CALM and PALL) of this approach will be presented at the upcoming annual meeting of the American Society of Hematology. The studies are a joint effort by Servier and Cellectis, which joined forces in the development of UCART19, an allogeneic CAR-T product for the treatment of CD19-expressing B-cell acute lymphoblastic leukemia.
Still, value remains an important consideration. If a therapy is expected to extend a pancreatic cancer patient’s life by a month, it’s probably valid to ask if that is cost effective, but if it is potentially curative for a patient with hematologic malignancy, it’s very hard to say they can’t access it, Dr. Heslop said.
Cost-saving proposals
Efforts to address the cost concerns, including proposals for novel payment strategies, are already emerging. One example involves an offer by Novartis to charge for Kymriah only if treated patients go into remission within 1 month. Details of the plan haven’t been released.
Another approach is being considered in Europe and involves a graduated payment system for an investigational regulatory T cell therapy for autoimmune disease, Dr. Maziarz said. For example, if the drug costs $1 million, the government might pay $200,000 the first year and then $100,000 per year if the patient is cured. “If the patient relapses, they can stop their payment, as cure was not achieved,” he explained.
In many discussions about value, the definition is based on quality-adjusted life years (QALY) gained, he said. A recent statement from the American College of Cardiology and the American Heart Association on cost/value methodology, for example, used $50,000 per QALY gained as the cut-off for a good investment. Costs of $50,000 to less than $150,000 per QALY were considered to be of intermediate value, and costs of $150,000 or greater per QALY gained were considered to be of low value.
“A number of payers are using these guidelines to determine what drugs they will put on their portfolio and make available to enrollees,” Dr. Maziarz said.
In anticipation of cost-related issues with CAR T-cell therapy, the Institute for Clinical and Economic Review (ICER) and its California Technology Assessment Forum (CTAP) put out a request for information and input regarding their intent to collaboratively initiate an assessment of CAR T-cell effectiveness and value, he said.
In the meantime, Dr. Maziarz said that most private insurers he’s been in contact with are planning coverage of CAR T-cell therapy but are working out the details of how to do it.
“It’s typically going to involve very, very strict guidelines for the patients who go on therapy – it’s not going to be a liberal use of the product. It will involve strict adherence to the label,” he said.
The real challenge, however, will be in the Medicare and Medicaid programs, because of the current nature of the reimbursement structures and lack of clear procedural codes to define the effort and cost of care associated with the application of these novel cell therapies.
Walid F. Gellad, MD, and Aaron S. Kesselheim, MD, anticipated some of these challenges in light of accelerated approval processes for expensive drugs and proposed in a May 2017 paper that government payers reimburse only the cost of manufacturing and some predetermined mark-up for such drugs until confirmatory trials demonstrate clinical benefit (N Engl J Med. 2017;376[21]:2001-04).
“Both Yescarta and Kymriah are approved with very, very, very limited data – 100 patients, 80 patients. They absolutely look promising. I was part of those studies, so I’m a believer, but the classic approach to determining success in the medical community is a randomized controlled trial,” Dr. Maziarz said.
The proposal by Dr. Gellad and Dr. Kesselheim acknowledged this, and said perhaps full payment isn’t warranted while the drugs remain in development and until they are proven to be a good investment.
Their proposal also calls for an economic impact analysis after 1-2 years on the market for all accelerated-approval pathway drugs that cost over a predetermined amount, timely and optimally designed confirmatory trials following accelerated approval to limit the period of uncertainty about the true clinical effect of the drug, and additional price concessions to public insurance programs for such drugs until the confirmatory trials are completed. Under this proposal, the unpaid portion of drug costs would be held in escrow until the drug’s efficacy is confirmed.
“I think what’s going to happen is that, as prices and costs go up for any therapy, that backlash will occur. These types of proposals to create solutions will come not from individual companies, but from the government,” Dr. Maziarz said. “I’m 100% excited about the work. I’m extremely excited to be part of the explorations. … I just still think we have to at least try to be aware and cognizant of the issues that we’ll be facing.”
Dr. Maziarz has received consulting fees from Novartis, Juno Therapeutics, and Kite Pharma. Dr. Heslop has received consulting fees from Novartis, has conducted research for Cell Medica and holds intellectual property rights/patent from Cell Medica, and has ownership interest in ViraCyte and Marker Therapeutics. Dr. June received royalties from Novartis, has conducted research for Novartis, and has ownership interest in Tmunity Therapeutics.
Chimeric antigen receptor (CAR) T-cell therapy has generated a great deal of excitement in recent months with the approval of Novartis’ Kymriah (tisagenlecleucel) for pediatric acute lymphoblastic leukemia and Kite Pharma’s Yescarta (axicabtagene ciloleucel) for relapsed/refractory large B-cell lymphoma in adults, and experts in the field foresee a wave of approvals for additional indications in the coming months.
“CAR T is coming unbelievably fast,” Richard Maziarz, MD, professor of medicine at Oregon Health and Science University, Portland, said in an interview.
In fact, a search of clinicaltrials.gov revealed 120 open CAR T-cell–based therapy trials for cancer and other conditions such as autoimmune diseases, he said.
Price tag pressure
During a plenary session on genetically modified cell therapies at the annual meeting of the Society for Immunotherapy of Cancer, experts and investigators provided a glimpse of what’s in store, including new targets and smarter targeting and combinations that incorporate CAR T-cell therapy to treat solid tumors.
The “list price” for tisagenlecleucel is $475,000, and the potential patient pool is in the hundreds. The price for axicabtagene ciloleucel is $373,000, with a potential market in the thousands. Taking this into account, the global CAR T market is estimated at about $72 million and is projected to expand to nearly $3.5 billion in the next decade, said Dr. Maziarz, who is also chair of the Value and Health Economics Interest Group of the American Society for Blood and Marrow Transplantation.
The market for adoptive cell therapy overall – including transplant, CAR T, natural killer cells, and cell vaccines – is projected by some individuals to be worth $30 billion by 2030, he added, noting, for the sake of comparison, that the total estimated U.S. expenditure for all cancer care in the United States in 2010 was $125 billion.
At the heart of the issue of cost is the matter of value, he said.
“You can talk about price, and you can talk about cost, but … what we want to do with our dollars is buy value – and quality and value are very hard to measure,” he said, noting that he expects public and governmental backlash, as was seen with prior high-cost treatments such as Sovaldi for hepatitis C and Glybera for lipoprotein lipase deficiency.
Value-based payment is a recurrent theme in medicine, and these treatments came under intense scrutiny for their high costs. Sovaldi, for example, costs approximately $90,000 for a treatment course. That sounds like a lot of money, but it cures the disease and can prevent long-term complications, Dr. Maziarz said. Still, it received a lot of negative press, and the backlash was severe.
“People do respond to price,” he said, noting that he predicts the same for CAR T-cell therapies.
The costs of CAR T-cell therapy, particularly when taking into consideration the costs that hospitals will incur given the lymphodepletion that patients experience and the after-care required, will likely exceed those of most stem cell transplants and could easily reach the $1 million-plus estimates, Helen Heslop, MD, professor of medicine and pediatrics and director of the Center for Cell and Gene Therapy at Baylor College of Medicine, Houston, said in an interview.
Aside from the research and development costs, these treatments also cost more to make than any others previously made, according to Carl H. June, MD, the Richard W. Vague Professor In Immunotherapy at the University of Pennsylvania, Philadelphia, and a pioneer in CAR T-cell research.
Dr. June predicted that costs will be forced down over time because of process improvements and competition. “What’s unknown is the time span on how long it will take,” he said in an interview.
Groups like the United Kingdom’s National Institute for Health and Care Excellence (NICE) are already looking at value-based approaches to providing CAR T-cell therapy, Dr. Heslop said.
“I think there will need to be a lot more comparative effectiveness analyses done,” she said. “I know my institution started to look at the cost in a child with ALL once they relapse, and when you look at all the downstream cost, even though [CAR T-cell therapy] sounds very expensive, as a one-time therapy versus much longer treatment, it may actually be value based,” she said.
When it comes to improving access, one of the approaches being studied is the use of universal cell banks as opposed to autologous cells for therapy. This “off-the-shelf” approach, much like the approach used in transfusion medicine, would allow for quicker availability of the cells to a greater number of patients, she said.
Dr. June who, along with Dr. Heslop, cochaired the SITC plenary session on genetically modified cell therapy, agreed, saying that if this approach works with T cells, it would radically change the CAR T landscape in terms of availability and, perhaps – eventually – cost.
Preliminary results from phase I studies (CALM and PALL) of this approach will be presented at the upcoming annual meeting of the American Society of Hematology. The studies are a joint effort by Servier and Cellectis, which joined forces in the development of UCART19, an allogeneic CAR-T product for the treatment of CD19-expressing B-cell acute lymphoblastic leukemia.
Still, value remains an important consideration. If a therapy is expected to extend a pancreatic cancer patient’s life by a month, it’s probably valid to ask if that is cost effective, but if it is potentially curative for a patient with hematologic malignancy, it’s very hard to say they can’t access it, Dr. Heslop said.
Cost-saving proposals
Efforts to address the cost concerns, including proposals for novel payment strategies, are already emerging. One example involves an offer by Novartis to charge for Kymriah only if treated patients go into remission within 1 month. Details of the plan haven’t been released.
Another approach is being considered in Europe and involves a graduated payment system for an investigational regulatory T cell therapy for autoimmune disease, Dr. Maziarz said. For example, if the drug costs $1 million, the government might pay $200,000 the first year and then $100,000 per year if the patient is cured. “If the patient relapses, they can stop their payment, as cure was not achieved,” he explained.
In many discussions about value, the definition is based on quality-adjusted life years (QALY) gained, he said. A recent statement from the American College of Cardiology and the American Heart Association on cost/value methodology, for example, used $50,000 per QALY gained as the cut-off for a good investment. Costs of $50,000 to less than $150,000 per QALY were considered to be of intermediate value, and costs of $150,000 or greater per QALY gained were considered to be of low value.
“A number of payers are using these guidelines to determine what drugs they will put on their portfolio and make available to enrollees,” Dr. Maziarz said.
In anticipation of cost-related issues with CAR T-cell therapy, the Institute for Clinical and Economic Review (ICER) and its California Technology Assessment Forum (CTAP) put out a request for information and input regarding their intent to collaboratively initiate an assessment of CAR T-cell effectiveness and value, he said.
In the meantime, Dr. Maziarz said that most private insurers he’s been in contact with are planning coverage of CAR T-cell therapy but are working out the details of how to do it.
“It’s typically going to involve very, very strict guidelines for the patients who go on therapy – it’s not going to be a liberal use of the product. It will involve strict adherence to the label,” he said.
The real challenge, however, will be in the Medicare and Medicaid programs, because of the current nature of the reimbursement structures and lack of clear procedural codes to define the effort and cost of care associated with the application of these novel cell therapies.
Walid F. Gellad, MD, and Aaron S. Kesselheim, MD, anticipated some of these challenges in light of accelerated approval processes for expensive drugs and proposed in a May 2017 paper that government payers reimburse only the cost of manufacturing and some predetermined mark-up for such drugs until confirmatory trials demonstrate clinical benefit (N Engl J Med. 2017;376[21]:2001-04).
“Both Yescarta and Kymriah are approved with very, very, very limited data – 100 patients, 80 patients. They absolutely look promising. I was part of those studies, so I’m a believer, but the classic approach to determining success in the medical community is a randomized controlled trial,” Dr. Maziarz said.
The proposal by Dr. Gellad and Dr. Kesselheim acknowledged this, and said perhaps full payment isn’t warranted while the drugs remain in development and until they are proven to be a good investment.
Their proposal also calls for an economic impact analysis after 1-2 years on the market for all accelerated-approval pathway drugs that cost over a predetermined amount, timely and optimally designed confirmatory trials following accelerated approval to limit the period of uncertainty about the true clinical effect of the drug, and additional price concessions to public insurance programs for such drugs until the confirmatory trials are completed. Under this proposal, the unpaid portion of drug costs would be held in escrow until the drug’s efficacy is confirmed.
“I think what’s going to happen is that, as prices and costs go up for any therapy, that backlash will occur. These types of proposals to create solutions will come not from individual companies, but from the government,” Dr. Maziarz said. “I’m 100% excited about the work. I’m extremely excited to be part of the explorations. … I just still think we have to at least try to be aware and cognizant of the issues that we’ll be facing.”
Dr. Maziarz has received consulting fees from Novartis, Juno Therapeutics, and Kite Pharma. Dr. Heslop has received consulting fees from Novartis, has conducted research for Cell Medica and holds intellectual property rights/patent from Cell Medica, and has ownership interest in ViraCyte and Marker Therapeutics. Dr. June received royalties from Novartis, has conducted research for Novartis, and has ownership interest in Tmunity Therapeutics.
Chimeric antigen receptor (CAR) T-cell therapy has generated a great deal of excitement in recent months with the approval of Novartis’ Kymriah (tisagenlecleucel) for pediatric acute lymphoblastic leukemia and Kite Pharma’s Yescarta (axicabtagene ciloleucel) for relapsed/refractory large B-cell lymphoma in adults, and experts in the field foresee a wave of approvals for additional indications in the coming months.
“CAR T is coming unbelievably fast,” Richard Maziarz, MD, professor of medicine at Oregon Health and Science University, Portland, said in an interview.
In fact, a search of clinicaltrials.gov revealed 120 open CAR T-cell–based therapy trials for cancer and other conditions such as autoimmune diseases, he said.
Price tag pressure
During a plenary session on genetically modified cell therapies at the annual meeting of the Society for Immunotherapy of Cancer, experts and investigators provided a glimpse of what’s in store, including new targets and smarter targeting and combinations that incorporate CAR T-cell therapy to treat solid tumors.
The “list price” for tisagenlecleucel is $475,000, and the potential patient pool is in the hundreds. The price for axicabtagene ciloleucel is $373,000, with a potential market in the thousands. Taking this into account, the global CAR T market is estimated at about $72 million and is projected to expand to nearly $3.5 billion in the next decade, said Dr. Maziarz, who is also chair of the Value and Health Economics Interest Group of the American Society for Blood and Marrow Transplantation.
The market for adoptive cell therapy overall – including transplant, CAR T, natural killer cells, and cell vaccines – is projected by some individuals to be worth $30 billion by 2030, he added, noting, for the sake of comparison, that the total estimated U.S. expenditure for all cancer care in the United States in 2010 was $125 billion.
At the heart of the issue of cost is the matter of value, he said.
“You can talk about price, and you can talk about cost, but … what we want to do with our dollars is buy value – and quality and value are very hard to measure,” he said, noting that he expects public and governmental backlash, as was seen with prior high-cost treatments such as Sovaldi for hepatitis C and Glybera for lipoprotein lipase deficiency.
Value-based payment is a recurrent theme in medicine, and these treatments came under intense scrutiny for their high costs. Sovaldi, for example, costs approximately $90,000 for a treatment course. That sounds like a lot of money, but it cures the disease and can prevent long-term complications, Dr. Maziarz said. Still, it received a lot of negative press, and the backlash was severe.
“People do respond to price,” he said, noting that he predicts the same for CAR T-cell therapies.
The costs of CAR T-cell therapy, particularly when taking into consideration the costs that hospitals will incur given the lymphodepletion that patients experience and the after-care required, will likely exceed those of most stem cell transplants and could easily reach the $1 million-plus estimates, Helen Heslop, MD, professor of medicine and pediatrics and director of the Center for Cell and Gene Therapy at Baylor College of Medicine, Houston, said in an interview.
Aside from the research and development costs, these treatments also cost more to make than any others previously made, according to Carl H. June, MD, the Richard W. Vague Professor In Immunotherapy at the University of Pennsylvania, Philadelphia, and a pioneer in CAR T-cell research.
Dr. June predicted that costs will be forced down over time because of process improvements and competition. “What’s unknown is the time span on how long it will take,” he said in an interview.
Groups like the United Kingdom’s National Institute for Health and Care Excellence (NICE) are already looking at value-based approaches to providing CAR T-cell therapy, Dr. Heslop said.
“I think there will need to be a lot more comparative effectiveness analyses done,” she said. “I know my institution started to look at the cost in a child with ALL once they relapse, and when you look at all the downstream cost, even though [CAR T-cell therapy] sounds very expensive, as a one-time therapy versus much longer treatment, it may actually be value based,” she said.
When it comes to improving access, one of the approaches being studied is the use of universal cell banks as opposed to autologous cells for therapy. This “off-the-shelf” approach, much like the approach used in transfusion medicine, would allow for quicker availability of the cells to a greater number of patients, she said.
Dr. June who, along with Dr. Heslop, cochaired the SITC plenary session on genetically modified cell therapy, agreed, saying that if this approach works with T cells, it would radically change the CAR T landscape in terms of availability and, perhaps – eventually – cost.
Preliminary results from phase I studies (CALM and PALL) of this approach will be presented at the upcoming annual meeting of the American Society of Hematology. The studies are a joint effort by Servier and Cellectis, which joined forces in the development of UCART19, an allogeneic CAR-T product for the treatment of CD19-expressing B-cell acute lymphoblastic leukemia.
Still, value remains an important consideration. If a therapy is expected to extend a pancreatic cancer patient’s life by a month, it’s probably valid to ask if that is cost effective, but if it is potentially curative for a patient with hematologic malignancy, it’s very hard to say they can’t access it, Dr. Heslop said.
Cost-saving proposals
Efforts to address the cost concerns, including proposals for novel payment strategies, are already emerging. One example involves an offer by Novartis to charge for Kymriah only if treated patients go into remission within 1 month. Details of the plan haven’t been released.
Another approach is being considered in Europe and involves a graduated payment system for an investigational regulatory T cell therapy for autoimmune disease, Dr. Maziarz said. For example, if the drug costs $1 million, the government might pay $200,000 the first year and then $100,000 per year if the patient is cured. “If the patient relapses, they can stop their payment, as cure was not achieved,” he explained.
In many discussions about value, the definition is based on quality-adjusted life years (QALY) gained, he said. A recent statement from the American College of Cardiology and the American Heart Association on cost/value methodology, for example, used $50,000 per QALY gained as the cut-off for a good investment. Costs of $50,000 to less than $150,000 per QALY were considered to be of intermediate value, and costs of $150,000 or greater per QALY gained were considered to be of low value.
“A number of payers are using these guidelines to determine what drugs they will put on their portfolio and make available to enrollees,” Dr. Maziarz said.
In anticipation of cost-related issues with CAR T-cell therapy, the Institute for Clinical and Economic Review (ICER) and its California Technology Assessment Forum (CTAP) put out a request for information and input regarding their intent to collaboratively initiate an assessment of CAR T-cell effectiveness and value, he said.
In the meantime, Dr. Maziarz said that most private insurers he’s been in contact with are planning coverage of CAR T-cell therapy but are working out the details of how to do it.
“It’s typically going to involve very, very strict guidelines for the patients who go on therapy – it’s not going to be a liberal use of the product. It will involve strict adherence to the label,” he said.
The real challenge, however, will be in the Medicare and Medicaid programs, because of the current nature of the reimbursement structures and lack of clear procedural codes to define the effort and cost of care associated with the application of these novel cell therapies.
Walid F. Gellad, MD, and Aaron S. Kesselheim, MD, anticipated some of these challenges in light of accelerated approval processes for expensive drugs and proposed in a May 2017 paper that government payers reimburse only the cost of manufacturing and some predetermined mark-up for such drugs until confirmatory trials demonstrate clinical benefit (N Engl J Med. 2017;376[21]:2001-04).
“Both Yescarta and Kymriah are approved with very, very, very limited data – 100 patients, 80 patients. They absolutely look promising. I was part of those studies, so I’m a believer, but the classic approach to determining success in the medical community is a randomized controlled trial,” Dr. Maziarz said.
The proposal by Dr. Gellad and Dr. Kesselheim acknowledged this, and said perhaps full payment isn’t warranted while the drugs remain in development and until they are proven to be a good investment.
Their proposal also calls for an economic impact analysis after 1-2 years on the market for all accelerated-approval pathway drugs that cost over a predetermined amount, timely and optimally designed confirmatory trials following accelerated approval to limit the period of uncertainty about the true clinical effect of the drug, and additional price concessions to public insurance programs for such drugs until the confirmatory trials are completed. Under this proposal, the unpaid portion of drug costs would be held in escrow until the drug’s efficacy is confirmed.
“I think what’s going to happen is that, as prices and costs go up for any therapy, that backlash will occur. These types of proposals to create solutions will come not from individual companies, but from the government,” Dr. Maziarz said. “I’m 100% excited about the work. I’m extremely excited to be part of the explorations. … I just still think we have to at least try to be aware and cognizant of the issues that we’ll be facing.”
Dr. Maziarz has received consulting fees from Novartis, Juno Therapeutics, and Kite Pharma. Dr. Heslop has received consulting fees from Novartis, has conducted research for Cell Medica and holds intellectual property rights/patent from Cell Medica, and has ownership interest in ViraCyte and Marker Therapeutics. Dr. June received royalties from Novartis, has conducted research for Novartis, and has ownership interest in Tmunity Therapeutics.
FDA authorizes next-generation sequencing test for tumor profiling
The Food and Drug Administration has authorized a new tumor profiling test that can identify a larger number of genetic mutations than available in any other test previously reviewed, the agency has announced.
The tumor profiling test, developed at Memorial Sloan Kettering Cancer Center and known as MSK-IMPACT (Integrated Mutation Profiling of Actionable Cancer Targets), is a custom targeted sequencing platform that uses exon capture and sequencing, so-called next-generation sequencing, to identify point mutations, small insertions and deletions, and microsatellite instability in tumor specimens. The assay involves hybridization capture and deep sequencing of all protein coding exons of 468 cancer-associated genes, as well as molecular changes in a tumor’s genomic makeup, according to the FDA announcement.
Unlike cancer diagnostic tests designed to determine the presence of one cancer biomarker for use with a single drug, the IMPACT test compares tumor tissue to a “normal” tissue or cell sample from the same patient to find genetic alterations that could potentially guide treatment options. However, the FDA said, the results of IMPACT are “not conclusive” for choosing a corresponding treatment.
Next-generation sequencing technologies can examine “hundreds, if not millions, of DNA variants at a time,” Jeffrey Shuren, MD, director of the FDA’s Center for Devices and Radiological Health, said in the announcement. “We are only at the beginning of realizing the true potential for these devices to assist patients and their health care providers in learning about the genetic underpinnings of their disease.”
Evaluations of IMPACT suggest the assay is “highly accurate” with a greater than 99% capability of detecting a mutation at a frequency of approximately 5%, according to the FDA.
In addition, detection of molecular changes, including microsatellite instability, were concordant more than 92% of the time when compared with traditional detection methods, the agency said.
Along with the marketing authorization for IMPACT, which was granted to Memorial Sloan Kettering Cancer Center, the agency announced that the New York State Department of Health has been accredited as an FDA third-party reviewer of in vitro diagnostics similar to IMPACT.
That action “paves the way” for efficient review and availability of other next-generation sequencing–based cancer profiling tools.
Allowing third parties to review next-generation sequencing–based tumor profiling tests will “reduce the burden on test developers and streamline the regulatory assessment of these types of innovative products,” FDA Commissioner Scott Gottlieb, MD, said in the announcement.
The Food and Drug Administration has authorized a new tumor profiling test that can identify a larger number of genetic mutations than available in any other test previously reviewed, the agency has announced.
The tumor profiling test, developed at Memorial Sloan Kettering Cancer Center and known as MSK-IMPACT (Integrated Mutation Profiling of Actionable Cancer Targets), is a custom targeted sequencing platform that uses exon capture and sequencing, so-called next-generation sequencing, to identify point mutations, small insertions and deletions, and microsatellite instability in tumor specimens. The assay involves hybridization capture and deep sequencing of all protein coding exons of 468 cancer-associated genes, as well as molecular changes in a tumor’s genomic makeup, according to the FDA announcement.
Unlike cancer diagnostic tests designed to determine the presence of one cancer biomarker for use with a single drug, the IMPACT test compares tumor tissue to a “normal” tissue or cell sample from the same patient to find genetic alterations that could potentially guide treatment options. However, the FDA said, the results of IMPACT are “not conclusive” for choosing a corresponding treatment.
Next-generation sequencing technologies can examine “hundreds, if not millions, of DNA variants at a time,” Jeffrey Shuren, MD, director of the FDA’s Center for Devices and Radiological Health, said in the announcement. “We are only at the beginning of realizing the true potential for these devices to assist patients and their health care providers in learning about the genetic underpinnings of their disease.”
Evaluations of IMPACT suggest the assay is “highly accurate” with a greater than 99% capability of detecting a mutation at a frequency of approximately 5%, according to the FDA.
In addition, detection of molecular changes, including microsatellite instability, were concordant more than 92% of the time when compared with traditional detection methods, the agency said.
Along with the marketing authorization for IMPACT, which was granted to Memorial Sloan Kettering Cancer Center, the agency announced that the New York State Department of Health has been accredited as an FDA third-party reviewer of in vitro diagnostics similar to IMPACT.
That action “paves the way” for efficient review and availability of other next-generation sequencing–based cancer profiling tools.
Allowing third parties to review next-generation sequencing–based tumor profiling tests will “reduce the burden on test developers and streamline the regulatory assessment of these types of innovative products,” FDA Commissioner Scott Gottlieb, MD, said in the announcement.
The Food and Drug Administration has authorized a new tumor profiling test that can identify a larger number of genetic mutations than available in any other test previously reviewed, the agency has announced.
The tumor profiling test, developed at Memorial Sloan Kettering Cancer Center and known as MSK-IMPACT (Integrated Mutation Profiling of Actionable Cancer Targets), is a custom targeted sequencing platform that uses exon capture and sequencing, so-called next-generation sequencing, to identify point mutations, small insertions and deletions, and microsatellite instability in tumor specimens. The assay involves hybridization capture and deep sequencing of all protein coding exons of 468 cancer-associated genes, as well as molecular changes in a tumor’s genomic makeup, according to the FDA announcement.
Unlike cancer diagnostic tests designed to determine the presence of one cancer biomarker for use with a single drug, the IMPACT test compares tumor tissue to a “normal” tissue or cell sample from the same patient to find genetic alterations that could potentially guide treatment options. However, the FDA said, the results of IMPACT are “not conclusive” for choosing a corresponding treatment.
Next-generation sequencing technologies can examine “hundreds, if not millions, of DNA variants at a time,” Jeffrey Shuren, MD, director of the FDA’s Center for Devices and Radiological Health, said in the announcement. “We are only at the beginning of realizing the true potential for these devices to assist patients and their health care providers in learning about the genetic underpinnings of their disease.”
Evaluations of IMPACT suggest the assay is “highly accurate” with a greater than 99% capability of detecting a mutation at a frequency of approximately 5%, according to the FDA.
In addition, detection of molecular changes, including microsatellite instability, were concordant more than 92% of the time when compared with traditional detection methods, the agency said.
Along with the marketing authorization for IMPACT, which was granted to Memorial Sloan Kettering Cancer Center, the agency announced that the New York State Department of Health has been accredited as an FDA third-party reviewer of in vitro diagnostics similar to IMPACT.
That action “paves the way” for efficient review and availability of other next-generation sequencing–based cancer profiling tools.
Allowing third parties to review next-generation sequencing–based tumor profiling tests will “reduce the burden on test developers and streamline the regulatory assessment of these types of innovative products,” FDA Commissioner Scott Gottlieb, MD, said in the announcement.
NCI-MATCH: Nivolumab shows promising activity in noncolorectal cancers
NATIONAL HARBOR, MD. – The immune checkpoint inhibitor nivolumab has promising activity in mismatch repair–deficient noncolorectal cancers, according to preliminary findings from the first sub-arm of the National Cancer Institute’s landmark Molecular Analysis for Therapy Choice (NCI-MATCH) trial.
NCI-MATCH is a 1,173-site precision medicine trial launched in 2015 to study targeted therapies for patients with relapsed/refractory solid tumors, lymphomas, and myelomas. In the first substudy (arm Z1D), the investigators identified 4,900 subjects with samples that could be tested for “actionable molecular abnormalities,” and from among those, they identified 77 with loss of mismatch repair proteins MLH1 or MSH2. Ultimately 47 patients were treated with nivolumab in the substudy.
The confirmed overall response rate was 24%, and an additional 27% of patients had stable disease, said Dr. Azad of Johns Hopkins University, Baltimore.
The patients had a median age of 60 years and were heavily pretreated with a median of three prior therapies. The most common histologies among them were endometrioid endometrial cancer (10 patients), prostate cancer (6 patients), and breast cancer (3 patients).
The safety and tolerability of treatment was as expected for single-agent nivolumab treatment. Toxicity was predominantly low-grade fatigue. Anemia was the most common grade 3 toxicity.
“DNA repair defects due to mismatch repair–deficiency are most commonly caused by silencing of mismatch repair proteins MLH1 or MSH2 and, a little less commonly, MSH6 or PMS2. This can happen through DNA mutation, as well as promoter methylation,” Dr. Azad explained. “In fact, nivolumab has already been tested in patients with mismatch repair–deficient colorectal cancer, both alone and in combination with anti-CTLA-4 ipilimumab ... in addition, pembrolizumab was approved earlier this year for pretreated mismatch repair–deficient cancer.”
“So this formed the nidus for our interest and hypothesis that nivolumab would also have activity in mismatch repair–deficient noncolorectal cancer,” she said.
Study subjects had relapsed/refractory cancers, good end-organ function, and good performance status. They were screened for molecular alterations by centralized testing on fresh biopsy tissue, and mismatch repair deficiency was defined through immunohistochemistry as loss of nuclear expression of MLH1 or MSH2. Patients with mismatch repair–deficient colorectal cancer were excluded.
Those in the nivolumab arm received 3 mg/kg every 2 weeks, and after cycle 4, they could be switched to receive treatment every 4 weeks. Imaging was performed every 2 weeks, and patients were allowed to remain in the study as long as their disease had not progressed. A caveat was that patients with progression within the first 24 weeks, but with no more than four new lesions or 40% increase in tumor index lesions, could remain in the study as long as they were clinically stable.
The overall response rate was compared against a null value of 5%.
“We enrolled 35 patients so that we could have 31 evaluable patients, looking for a signal of 5 or greater responses in that patient group to conclude that the arm was promising and worth further testing,” Dr. Azad said. “This gave us 91.8% power to conclude that an agent was promising if the overall response was truly 25%.”
The study met its primary endpoint, with 8 responses out of 34 evaluable patients, she reported.
“Of note, we had five more patients that had unconfirmed responses. Two of those remained on study at the time of data cutoff, so these response numbers may change as the study matures,” she said.
The disease control rate was 56%, and benefit was seen across tumor histologies, she noted.
“The duration of benefit was compelling for these patients,” she said. “The median time to response was 2.1 cycles, and the 6-month progression-free survival was 49%.”
The median duration of response has not been reached.
Follow-up is ongoing, and 12 patients are enrolled in an expansion cohort; results should be reported within the next year.
“Future work includes interrogating tumor tissue and blood to identify possible predictive markers of response and resistance,” Dr. Azad concluded.
Dr. Azad reported having no disclosures.
NATIONAL HARBOR, MD. – The immune checkpoint inhibitor nivolumab has promising activity in mismatch repair–deficient noncolorectal cancers, according to preliminary findings from the first sub-arm of the National Cancer Institute’s landmark Molecular Analysis for Therapy Choice (NCI-MATCH) trial.
NCI-MATCH is a 1,173-site precision medicine trial launched in 2015 to study targeted therapies for patients with relapsed/refractory solid tumors, lymphomas, and myelomas. In the first substudy (arm Z1D), the investigators identified 4,900 subjects with samples that could be tested for “actionable molecular abnormalities,” and from among those, they identified 77 with loss of mismatch repair proteins MLH1 or MSH2. Ultimately 47 patients were treated with nivolumab in the substudy.
The confirmed overall response rate was 24%, and an additional 27% of patients had stable disease, said Dr. Azad of Johns Hopkins University, Baltimore.
The patients had a median age of 60 years and were heavily pretreated with a median of three prior therapies. The most common histologies among them were endometrioid endometrial cancer (10 patients), prostate cancer (6 patients), and breast cancer (3 patients).
The safety and tolerability of treatment was as expected for single-agent nivolumab treatment. Toxicity was predominantly low-grade fatigue. Anemia was the most common grade 3 toxicity.
“DNA repair defects due to mismatch repair–deficiency are most commonly caused by silencing of mismatch repair proteins MLH1 or MSH2 and, a little less commonly, MSH6 or PMS2. This can happen through DNA mutation, as well as promoter methylation,” Dr. Azad explained. “In fact, nivolumab has already been tested in patients with mismatch repair–deficient colorectal cancer, both alone and in combination with anti-CTLA-4 ipilimumab ... in addition, pembrolizumab was approved earlier this year for pretreated mismatch repair–deficient cancer.”
“So this formed the nidus for our interest and hypothesis that nivolumab would also have activity in mismatch repair–deficient noncolorectal cancer,” she said.
Study subjects had relapsed/refractory cancers, good end-organ function, and good performance status. They were screened for molecular alterations by centralized testing on fresh biopsy tissue, and mismatch repair deficiency was defined through immunohistochemistry as loss of nuclear expression of MLH1 or MSH2. Patients with mismatch repair–deficient colorectal cancer were excluded.
Those in the nivolumab arm received 3 mg/kg every 2 weeks, and after cycle 4, they could be switched to receive treatment every 4 weeks. Imaging was performed every 2 weeks, and patients were allowed to remain in the study as long as their disease had not progressed. A caveat was that patients with progression within the first 24 weeks, but with no more than four new lesions or 40% increase in tumor index lesions, could remain in the study as long as they were clinically stable.
The overall response rate was compared against a null value of 5%.
“We enrolled 35 patients so that we could have 31 evaluable patients, looking for a signal of 5 or greater responses in that patient group to conclude that the arm was promising and worth further testing,” Dr. Azad said. “This gave us 91.8% power to conclude that an agent was promising if the overall response was truly 25%.”
The study met its primary endpoint, with 8 responses out of 34 evaluable patients, she reported.
“Of note, we had five more patients that had unconfirmed responses. Two of those remained on study at the time of data cutoff, so these response numbers may change as the study matures,” she said.
The disease control rate was 56%, and benefit was seen across tumor histologies, she noted.
“The duration of benefit was compelling for these patients,” she said. “The median time to response was 2.1 cycles, and the 6-month progression-free survival was 49%.”
The median duration of response has not been reached.
Follow-up is ongoing, and 12 patients are enrolled in an expansion cohort; results should be reported within the next year.
“Future work includes interrogating tumor tissue and blood to identify possible predictive markers of response and resistance,” Dr. Azad concluded.
Dr. Azad reported having no disclosures.
NATIONAL HARBOR, MD. – The immune checkpoint inhibitor nivolumab has promising activity in mismatch repair–deficient noncolorectal cancers, according to preliminary findings from the first sub-arm of the National Cancer Institute’s landmark Molecular Analysis for Therapy Choice (NCI-MATCH) trial.
NCI-MATCH is a 1,173-site precision medicine trial launched in 2015 to study targeted therapies for patients with relapsed/refractory solid tumors, lymphomas, and myelomas. In the first substudy (arm Z1D), the investigators identified 4,900 subjects with samples that could be tested for “actionable molecular abnormalities,” and from among those, they identified 77 with loss of mismatch repair proteins MLH1 or MSH2. Ultimately 47 patients were treated with nivolumab in the substudy.
The confirmed overall response rate was 24%, and an additional 27% of patients had stable disease, said Dr. Azad of Johns Hopkins University, Baltimore.
The patients had a median age of 60 years and were heavily pretreated with a median of three prior therapies. The most common histologies among them were endometrioid endometrial cancer (10 patients), prostate cancer (6 patients), and breast cancer (3 patients).
The safety and tolerability of treatment was as expected for single-agent nivolumab treatment. Toxicity was predominantly low-grade fatigue. Anemia was the most common grade 3 toxicity.
“DNA repair defects due to mismatch repair–deficiency are most commonly caused by silencing of mismatch repair proteins MLH1 or MSH2 and, a little less commonly, MSH6 or PMS2. This can happen through DNA mutation, as well as promoter methylation,” Dr. Azad explained. “In fact, nivolumab has already been tested in patients with mismatch repair–deficient colorectal cancer, both alone and in combination with anti-CTLA-4 ipilimumab ... in addition, pembrolizumab was approved earlier this year for pretreated mismatch repair–deficient cancer.”
“So this formed the nidus for our interest and hypothesis that nivolumab would also have activity in mismatch repair–deficient noncolorectal cancer,” she said.
Study subjects had relapsed/refractory cancers, good end-organ function, and good performance status. They were screened for molecular alterations by centralized testing on fresh biopsy tissue, and mismatch repair deficiency was defined through immunohistochemistry as loss of nuclear expression of MLH1 or MSH2. Patients with mismatch repair–deficient colorectal cancer were excluded.
Those in the nivolumab arm received 3 mg/kg every 2 weeks, and after cycle 4, they could be switched to receive treatment every 4 weeks. Imaging was performed every 2 weeks, and patients were allowed to remain in the study as long as their disease had not progressed. A caveat was that patients with progression within the first 24 weeks, but with no more than four new lesions or 40% increase in tumor index lesions, could remain in the study as long as they were clinically stable.
The overall response rate was compared against a null value of 5%.
“We enrolled 35 patients so that we could have 31 evaluable patients, looking for a signal of 5 or greater responses in that patient group to conclude that the arm was promising and worth further testing,” Dr. Azad said. “This gave us 91.8% power to conclude that an agent was promising if the overall response was truly 25%.”
The study met its primary endpoint, with 8 responses out of 34 evaluable patients, she reported.
“Of note, we had five more patients that had unconfirmed responses. Two of those remained on study at the time of data cutoff, so these response numbers may change as the study matures,” she said.
The disease control rate was 56%, and benefit was seen across tumor histologies, she noted.
“The duration of benefit was compelling for these patients,” she said. “The median time to response was 2.1 cycles, and the 6-month progression-free survival was 49%.”
The median duration of response has not been reached.
Follow-up is ongoing, and 12 patients are enrolled in an expansion cohort; results should be reported within the next year.
“Future work includes interrogating tumor tissue and blood to identify possible predictive markers of response and resistance,” Dr. Azad concluded.
Dr. Azad reported having no disclosures.
AT SITC 2017
Key clinical point:
Major finding: The confirmed overall response rate was 24%, and an additional 27% of patients had stable disease.
Data source: Arm Z1D (35 patients) of the NCI-MATCH trial.
Disclosures: Dr. Azad reported having no disclosures.
Gut bacteria influenced response to checkpoint inhibitors
The gut microbome may influence responses to immune checkpoint inhibitors, based on results from two studies, and one of the investigators is now gearing up for the next step - evaluating in a clinical trial whether altering the microflora will actually improve responses.
In the first study, investigators carried out a series of experiments using fecal microbiome samples from patients with metastatic melanoma embarking on therapy with a PD-1 (programmed cell death protein 1) inhibitor.
“In melanoma patients, there were differential signals in the gut microbiome of responders versus nonresponders, and I think the clincher was when we transplanted fecal samples from responders to nonresponders in germ-free mice, essentially reconstituting the microbiome and showing that it equally affected the systemic immunity and antitumor immunity when we implanted tumors, as well as response to checkpoint blockade,” lead author Jennifer A. Wargo, MD, MMSc, of the University of Texas MD Anderson Cancer Center in Houston, said in an interview.
Dr. Wargo and her colleagues first collected buccal and fecal microbiome samples from 112 patients with metastatic melanoma before they began therapy with a PD-1 inhibitor. After performing taxonomic profiling on all samples, they found that there was a clustering effect by response status in the gut microbiome, but not the oral microbiome, and because changes in the oral microbiome did not appear to be related to treatment response, they focused on the gut.
When Dr. Wargo and her colleagues studied the posttherapy microbiomes of 43 patients (30 responders and 13 nonresponders) according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1), they found that the responders had a significantly higher degree of alpha diversity, a measure of species diversity within a specific environment, compared with nonresponders (P less than .01). In addition, responders had a relative abundance of Ruminococcaceae, commonly occurring gut microbes that break down complex carbohydrates, the investigators reported (Science. 2017 Nov. 2. doi: 10.1126/science.aan4236).
They found that patients whose microbiomes were diverse in general, and in particular were enriched with Faecalibacterium and Clostridiales species, were more likely to respond to immunotherapy with a PD-1 inhibitor and have a longer duration of progression-free survival. In contrast, patients whose microbiomes were more enriched with Bacteroidales species were more likely to be nonresponders.
To get a better understanding of the mechanisms whereby gut bacteria may influence response to PD-1 inhibitors, they performed metagenomic analysis on samples from 14 responders and 11 nonresponders, and found that responders had micro-organisms predominantly associated with anabolic functions that may support host immunity, whereas nonresponders had microbiomes where catabolic functions were more common.
The investigators next performed immune profiling, and found that both systemic immunity and local immunity in the tumor microenvironment in responders were associated with the aforementioned favorable gut microbiome.
The researchers then transplanted feces from the human donors into germ-free mice and then injected tumor cells into the mice, and found that tumor growth was significantly reduced, and response to PD-1 inhibition was significantly enhanced, in mice who received feces from responders.
“An obvious next step is to run a clinical trial to test the hypothesis that by modulating the microbiome, you can actually enhance responses to therapy,” Dr. Wargo said. Details of the clinical trial are still being worked out, but will likely involve fecal transfers and other mechanisms for modulating the microbiome in hopes of improving responses to PD-1 inhibitors.
“It’s going to be a very biomarker-heavy trial,” she said. “We’re going to look, certainly, for changes in the microbiome, and will also do a lot of profiling in the blood, the tumor, and in the microbiome to see if there are changes that occur by modulating that microbiome. Then of course we’ll look for differences in response rates in patients as well.”
Bacteria also affect epithelial cancers
In a separate study, also published in Science, investigators led by Bertrand Routy, MD, of the Gustave Roussy Cancer Institute in Villejuif, France, reported that patients with non–small cell lung cancer and urothelial carcinoma who had previously used systemic antibiotics had reduced survival when treated with a PD-1 inhibitor, compared with patients who had never taken antibiotics (Science. 2017 Nov. 2 doi: 10.1126/science.aan3706).
Analysis of the gut microbiome in these patients showed that higher levels of Akkermansia muciniphila were associated with the best clinical outcomes, with the species detectable in the microbiome of 69% of patients who had partial responses to anti–PD-1 therapy, and in 58% of those with stable disease. In contrast, the bacterium was detectable in only 34% of patients who experienced disease progression.
As in the experiments by Dr. Wargo and her associates, when the French investigators first treated mice with antibiotics and then gave them oral supplements containing the bacteria, the supplements restored response to PD-1 blockade,
“We conclude from the study that the gut microbiome markedly influences the outcome of PD-1 blockade in mice and patients,” Dr. Routy and his associates wrote.
They acknowledged that the mechanism whereby a common organism such as Akkermansia muciniphila might have an immunomodulatory effect is still unknown,
“Irrespective of these remaining questions, our findings suggest that the microbiome governs the cancer-immune set point of cancer-bearing individuals and offer[s] novel avenues for manipulating the gut ecosystem to circumvent primary resistance to [immune checkpoint inhibitors],” they wrote.
The study by Dr. Wargo and her colleagues was supported by contributions to the University of Texas MD Anderson Melanoma Moon Shots program. Dr. Wargo is supported by the Binational Science Foundation, Melanoma Research Alliance, Stand Up to Cancer, and the MDACC Melanoma Moon Shots Program. The work by Dr. Routy and his associates was supported by the Goustave Roussy Cancer Institute and McGill University. Coauthors were supported by the National Cancer Institute of France and other agencies and philanthropies.
The gut microbome may influence responses to immune checkpoint inhibitors, based on results from two studies, and one of the investigators is now gearing up for the next step - evaluating in a clinical trial whether altering the microflora will actually improve responses.
In the first study, investigators carried out a series of experiments using fecal microbiome samples from patients with metastatic melanoma embarking on therapy with a PD-1 (programmed cell death protein 1) inhibitor.
“In melanoma patients, there were differential signals in the gut microbiome of responders versus nonresponders, and I think the clincher was when we transplanted fecal samples from responders to nonresponders in germ-free mice, essentially reconstituting the microbiome and showing that it equally affected the systemic immunity and antitumor immunity when we implanted tumors, as well as response to checkpoint blockade,” lead author Jennifer A. Wargo, MD, MMSc, of the University of Texas MD Anderson Cancer Center in Houston, said in an interview.
Dr. Wargo and her colleagues first collected buccal and fecal microbiome samples from 112 patients with metastatic melanoma before they began therapy with a PD-1 inhibitor. After performing taxonomic profiling on all samples, they found that there was a clustering effect by response status in the gut microbiome, but not the oral microbiome, and because changes in the oral microbiome did not appear to be related to treatment response, they focused on the gut.
When Dr. Wargo and her colleagues studied the posttherapy microbiomes of 43 patients (30 responders and 13 nonresponders) according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1), they found that the responders had a significantly higher degree of alpha diversity, a measure of species diversity within a specific environment, compared with nonresponders (P less than .01). In addition, responders had a relative abundance of Ruminococcaceae, commonly occurring gut microbes that break down complex carbohydrates, the investigators reported (Science. 2017 Nov. 2. doi: 10.1126/science.aan4236).
They found that patients whose microbiomes were diverse in general, and in particular were enriched with Faecalibacterium and Clostridiales species, were more likely to respond to immunotherapy with a PD-1 inhibitor and have a longer duration of progression-free survival. In contrast, patients whose microbiomes were more enriched with Bacteroidales species were more likely to be nonresponders.
To get a better understanding of the mechanisms whereby gut bacteria may influence response to PD-1 inhibitors, they performed metagenomic analysis on samples from 14 responders and 11 nonresponders, and found that responders had micro-organisms predominantly associated with anabolic functions that may support host immunity, whereas nonresponders had microbiomes where catabolic functions were more common.
The investigators next performed immune profiling, and found that both systemic immunity and local immunity in the tumor microenvironment in responders were associated with the aforementioned favorable gut microbiome.
The researchers then transplanted feces from the human donors into germ-free mice and then injected tumor cells into the mice, and found that tumor growth was significantly reduced, and response to PD-1 inhibition was significantly enhanced, in mice who received feces from responders.
“An obvious next step is to run a clinical trial to test the hypothesis that by modulating the microbiome, you can actually enhance responses to therapy,” Dr. Wargo said. Details of the clinical trial are still being worked out, but will likely involve fecal transfers and other mechanisms for modulating the microbiome in hopes of improving responses to PD-1 inhibitors.
“It’s going to be a very biomarker-heavy trial,” she said. “We’re going to look, certainly, for changes in the microbiome, and will also do a lot of profiling in the blood, the tumor, and in the microbiome to see if there are changes that occur by modulating that microbiome. Then of course we’ll look for differences in response rates in patients as well.”
Bacteria also affect epithelial cancers
In a separate study, also published in Science, investigators led by Bertrand Routy, MD, of the Gustave Roussy Cancer Institute in Villejuif, France, reported that patients with non–small cell lung cancer and urothelial carcinoma who had previously used systemic antibiotics had reduced survival when treated with a PD-1 inhibitor, compared with patients who had never taken antibiotics (Science. 2017 Nov. 2 doi: 10.1126/science.aan3706).
Analysis of the gut microbiome in these patients showed that higher levels of Akkermansia muciniphila were associated with the best clinical outcomes, with the species detectable in the microbiome of 69% of patients who had partial responses to anti–PD-1 therapy, and in 58% of those with stable disease. In contrast, the bacterium was detectable in only 34% of patients who experienced disease progression.
As in the experiments by Dr. Wargo and her associates, when the French investigators first treated mice with antibiotics and then gave them oral supplements containing the bacteria, the supplements restored response to PD-1 blockade,
“We conclude from the study that the gut microbiome markedly influences the outcome of PD-1 blockade in mice and patients,” Dr. Routy and his associates wrote.
They acknowledged that the mechanism whereby a common organism such as Akkermansia muciniphila might have an immunomodulatory effect is still unknown,
“Irrespective of these remaining questions, our findings suggest that the microbiome governs the cancer-immune set point of cancer-bearing individuals and offer[s] novel avenues for manipulating the gut ecosystem to circumvent primary resistance to [immune checkpoint inhibitors],” they wrote.
The study by Dr. Wargo and her colleagues was supported by contributions to the University of Texas MD Anderson Melanoma Moon Shots program. Dr. Wargo is supported by the Binational Science Foundation, Melanoma Research Alliance, Stand Up to Cancer, and the MDACC Melanoma Moon Shots Program. The work by Dr. Routy and his associates was supported by the Goustave Roussy Cancer Institute and McGill University. Coauthors were supported by the National Cancer Institute of France and other agencies and philanthropies.
The gut microbome may influence responses to immune checkpoint inhibitors, based on results from two studies, and one of the investigators is now gearing up for the next step - evaluating in a clinical trial whether altering the microflora will actually improve responses.
In the first study, investigators carried out a series of experiments using fecal microbiome samples from patients with metastatic melanoma embarking on therapy with a PD-1 (programmed cell death protein 1) inhibitor.
“In melanoma patients, there were differential signals in the gut microbiome of responders versus nonresponders, and I think the clincher was when we transplanted fecal samples from responders to nonresponders in germ-free mice, essentially reconstituting the microbiome and showing that it equally affected the systemic immunity and antitumor immunity when we implanted tumors, as well as response to checkpoint blockade,” lead author Jennifer A. Wargo, MD, MMSc, of the University of Texas MD Anderson Cancer Center in Houston, said in an interview.
Dr. Wargo and her colleagues first collected buccal and fecal microbiome samples from 112 patients with metastatic melanoma before they began therapy with a PD-1 inhibitor. After performing taxonomic profiling on all samples, they found that there was a clustering effect by response status in the gut microbiome, but not the oral microbiome, and because changes in the oral microbiome did not appear to be related to treatment response, they focused on the gut.
When Dr. Wargo and her colleagues studied the posttherapy microbiomes of 43 patients (30 responders and 13 nonresponders) according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1), they found that the responders had a significantly higher degree of alpha diversity, a measure of species diversity within a specific environment, compared with nonresponders (P less than .01). In addition, responders had a relative abundance of Ruminococcaceae, commonly occurring gut microbes that break down complex carbohydrates, the investigators reported (Science. 2017 Nov. 2. doi: 10.1126/science.aan4236).
They found that patients whose microbiomes were diverse in general, and in particular were enriched with Faecalibacterium and Clostridiales species, were more likely to respond to immunotherapy with a PD-1 inhibitor and have a longer duration of progression-free survival. In contrast, patients whose microbiomes were more enriched with Bacteroidales species were more likely to be nonresponders.
To get a better understanding of the mechanisms whereby gut bacteria may influence response to PD-1 inhibitors, they performed metagenomic analysis on samples from 14 responders and 11 nonresponders, and found that responders had micro-organisms predominantly associated with anabolic functions that may support host immunity, whereas nonresponders had microbiomes where catabolic functions were more common.
The investigators next performed immune profiling, and found that both systemic immunity and local immunity in the tumor microenvironment in responders were associated with the aforementioned favorable gut microbiome.
The researchers then transplanted feces from the human donors into germ-free mice and then injected tumor cells into the mice, and found that tumor growth was significantly reduced, and response to PD-1 inhibition was significantly enhanced, in mice who received feces from responders.
“An obvious next step is to run a clinical trial to test the hypothesis that by modulating the microbiome, you can actually enhance responses to therapy,” Dr. Wargo said. Details of the clinical trial are still being worked out, but will likely involve fecal transfers and other mechanisms for modulating the microbiome in hopes of improving responses to PD-1 inhibitors.
“It’s going to be a very biomarker-heavy trial,” she said. “We’re going to look, certainly, for changes in the microbiome, and will also do a lot of profiling in the blood, the tumor, and in the microbiome to see if there are changes that occur by modulating that microbiome. Then of course we’ll look for differences in response rates in patients as well.”
Bacteria also affect epithelial cancers
In a separate study, also published in Science, investigators led by Bertrand Routy, MD, of the Gustave Roussy Cancer Institute in Villejuif, France, reported that patients with non–small cell lung cancer and urothelial carcinoma who had previously used systemic antibiotics had reduced survival when treated with a PD-1 inhibitor, compared with patients who had never taken antibiotics (Science. 2017 Nov. 2 doi: 10.1126/science.aan3706).
Analysis of the gut microbiome in these patients showed that higher levels of Akkermansia muciniphila were associated with the best clinical outcomes, with the species detectable in the microbiome of 69% of patients who had partial responses to anti–PD-1 therapy, and in 58% of those with stable disease. In contrast, the bacterium was detectable in only 34% of patients who experienced disease progression.
As in the experiments by Dr. Wargo and her associates, when the French investigators first treated mice with antibiotics and then gave them oral supplements containing the bacteria, the supplements restored response to PD-1 blockade,
“We conclude from the study that the gut microbiome markedly influences the outcome of PD-1 blockade in mice and patients,” Dr. Routy and his associates wrote.
They acknowledged that the mechanism whereby a common organism such as Akkermansia muciniphila might have an immunomodulatory effect is still unknown,
“Irrespective of these remaining questions, our findings suggest that the microbiome governs the cancer-immune set point of cancer-bearing individuals and offer[s] novel avenues for manipulating the gut ecosystem to circumvent primary resistance to [immune checkpoint inhibitors],” they wrote.
The study by Dr. Wargo and her colleagues was supported by contributions to the University of Texas MD Anderson Melanoma Moon Shots program. Dr. Wargo is supported by the Binational Science Foundation, Melanoma Research Alliance, Stand Up to Cancer, and the MDACC Melanoma Moon Shots Program. The work by Dr. Routy and his associates was supported by the Goustave Roussy Cancer Institute and McGill University. Coauthors were supported by the National Cancer Institute of France and other agencies and philanthropies.
FROM SCIENCE
Key clinical point: Modulating the gut microbome may improve responses to immune checkpoint inhibitors in patients with advanced melanoma, non–small cell lung cancer, and urothelial carcinoma.
Major finding: Responders to a checkpoint inhibitor had a significantly higher degree of alpha diversity, a measure of species diversity within a specific environment, compared with nonresponders (P less than .01).
Data source: A series of studies using microbiome samples from cancer patients receiving immune checkpoint inhibitors.
Disclosures: The study by Dr. Wargo and her colleagues was supported by contributions to the University of Texas MD Anderson Melanoma Moon Shots Program. Dr. Wargo is supported by the Binational Science Foundation, Melanoma Research Alliance, Stand Up to Cancer, and the MDACC Melanoma Moon Shots Program. The work by Dr. Routy and his colleagues was supported by the Goustave Roussy Cancer Institute and McGill University. Coauthors were supported by the National Cancer Institute of France and other agencies and philanthropies.
CheckMate 214: Updated results for RCC focus on PD-L1 expression, QOL
NATIONAL HARBOR, MD. – The benefits of combined treatment with the immune checkpoint inhibitors nivolumab and ipilimumab (nivo/ipi) vs. the tyrosine kinase inhibitor sunitinib as demonstrated in intermediate- to poor-risk renal cell carcinoma patients in the CheckMate 214 trial were observed across baseline programmed death–ligand 1 (PD-L1) expression levels, according to subgroup analyses from the open-label phase 3 trial.
However, those with PD-L1–positive tumors – defined as tumors with PD-L1 expression in 1% or more of cells – had improved outcomes, compared with those with PD-L1–negative tumors. This was true for all three co-primary endpoints of the study: overall response rate, progression-free survival, and overall survival, Robert J. Motzer, MD, reported at the annual meeting of the Society for Immunotherapy of Cancer.
“For progression-free survival ... [there was] a strong signal in patients who were PD-L1 expression–positive, but not so in those with PD-L1–negative tumors,” he said (P = .003 and .9670, respectively). “In the overall survival endpoint ... patients benefited with longer survival with nivo/ipi, regardless of PD-L1 expression, but the relative benefit seemed higher in patients expressing PD-L1 (P less than .0001 and .0249, respectively).”
The primary efficacy results of CheckMate 214 were reported in September at the European Society of Medical Oncology. The study enrolled 1,096 patients with treatment-naive advanced or metastatic clear-cell renal cell carcinoma with measurable disease and adequate performance status who were stratified by prognostic score and geographical region and randomly assigned to receive either 3 mg/kg nivolumab and 1 mg/kg ipilimumab every 3 weeks for four doses, then 3 mg/kg nivolumab monotherapy every other week, or 50 mg oral sunitinib once daily for 4 weeks in a 6-week cycle. Treatment continued until patients progressed or experienced unacceptable toxicity.
Most of the patients in the study (847 of 1,096) had intermediate- to poor-risk disease and most of those (about 70%) were PD-L1 negative.
Overall, the study met two of the primary endpoints, demonstrating superior overall survival and overall response rates with nivo/ipi vs. sunitinib in intermediate/poor-risk patients with treatment-naive advanced renal cell carcinoma, Dr. Motzer said.
In addition to presenting the subgroup data regarding outcomes across PD-L1 expression levels at the meeting, he also presented new data showing improved self-reported quality of life among patients treated with nivo/ipi vs. sunitinib. Quality of life was measured using the National Comprehensive Cancer Network/ Functional Assessment Of Cancer Therapy–Kidney Symptom Index 19 questionnaire, which “looks at questions particularly relevant to renal cell carcinoma patients,” he said.
The mean change in questionnaire scores from baseline was consistently better in the nivo/ipi arm. At 104 weeks the mean change was about +5 points with nivo/ipi vs. about –7 points with sunitinib.
“These results support the use of nivo/ipi as a new first-line standard of care option for patients with intermediate/poor-risk advanced [renal cell carcinoma],” he concluded.
CheckMate 214 was funded by Bristol-Myers Squibb and Ono Pharmaceutical. Dr. Motzer reported ownership interest in Armo Biosciences.
NATIONAL HARBOR, MD. – The benefits of combined treatment with the immune checkpoint inhibitors nivolumab and ipilimumab (nivo/ipi) vs. the tyrosine kinase inhibitor sunitinib as demonstrated in intermediate- to poor-risk renal cell carcinoma patients in the CheckMate 214 trial were observed across baseline programmed death–ligand 1 (PD-L1) expression levels, according to subgroup analyses from the open-label phase 3 trial.
However, those with PD-L1–positive tumors – defined as tumors with PD-L1 expression in 1% or more of cells – had improved outcomes, compared with those with PD-L1–negative tumors. This was true for all three co-primary endpoints of the study: overall response rate, progression-free survival, and overall survival, Robert J. Motzer, MD, reported at the annual meeting of the Society for Immunotherapy of Cancer.
“For progression-free survival ... [there was] a strong signal in patients who were PD-L1 expression–positive, but not so in those with PD-L1–negative tumors,” he said (P = .003 and .9670, respectively). “In the overall survival endpoint ... patients benefited with longer survival with nivo/ipi, regardless of PD-L1 expression, but the relative benefit seemed higher in patients expressing PD-L1 (P less than .0001 and .0249, respectively).”
The primary efficacy results of CheckMate 214 were reported in September at the European Society of Medical Oncology. The study enrolled 1,096 patients with treatment-naive advanced or metastatic clear-cell renal cell carcinoma with measurable disease and adequate performance status who were stratified by prognostic score and geographical region and randomly assigned to receive either 3 mg/kg nivolumab and 1 mg/kg ipilimumab every 3 weeks for four doses, then 3 mg/kg nivolumab monotherapy every other week, or 50 mg oral sunitinib once daily for 4 weeks in a 6-week cycle. Treatment continued until patients progressed or experienced unacceptable toxicity.
Most of the patients in the study (847 of 1,096) had intermediate- to poor-risk disease and most of those (about 70%) were PD-L1 negative.
Overall, the study met two of the primary endpoints, demonstrating superior overall survival and overall response rates with nivo/ipi vs. sunitinib in intermediate/poor-risk patients with treatment-naive advanced renal cell carcinoma, Dr. Motzer said.
In addition to presenting the subgroup data regarding outcomes across PD-L1 expression levels at the meeting, he also presented new data showing improved self-reported quality of life among patients treated with nivo/ipi vs. sunitinib. Quality of life was measured using the National Comprehensive Cancer Network/ Functional Assessment Of Cancer Therapy–Kidney Symptom Index 19 questionnaire, which “looks at questions particularly relevant to renal cell carcinoma patients,” he said.
The mean change in questionnaire scores from baseline was consistently better in the nivo/ipi arm. At 104 weeks the mean change was about +5 points with nivo/ipi vs. about –7 points with sunitinib.
“These results support the use of nivo/ipi as a new first-line standard of care option for patients with intermediate/poor-risk advanced [renal cell carcinoma],” he concluded.
CheckMate 214 was funded by Bristol-Myers Squibb and Ono Pharmaceutical. Dr. Motzer reported ownership interest in Armo Biosciences.
NATIONAL HARBOR, MD. – The benefits of combined treatment with the immune checkpoint inhibitors nivolumab and ipilimumab (nivo/ipi) vs. the tyrosine kinase inhibitor sunitinib as demonstrated in intermediate- to poor-risk renal cell carcinoma patients in the CheckMate 214 trial were observed across baseline programmed death–ligand 1 (PD-L1) expression levels, according to subgroup analyses from the open-label phase 3 trial.
However, those with PD-L1–positive tumors – defined as tumors with PD-L1 expression in 1% or more of cells – had improved outcomes, compared with those with PD-L1–negative tumors. This was true for all three co-primary endpoints of the study: overall response rate, progression-free survival, and overall survival, Robert J. Motzer, MD, reported at the annual meeting of the Society for Immunotherapy of Cancer.
“For progression-free survival ... [there was] a strong signal in patients who were PD-L1 expression–positive, but not so in those with PD-L1–negative tumors,” he said (P = .003 and .9670, respectively). “In the overall survival endpoint ... patients benefited with longer survival with nivo/ipi, regardless of PD-L1 expression, but the relative benefit seemed higher in patients expressing PD-L1 (P less than .0001 and .0249, respectively).”
The primary efficacy results of CheckMate 214 were reported in September at the European Society of Medical Oncology. The study enrolled 1,096 patients with treatment-naive advanced or metastatic clear-cell renal cell carcinoma with measurable disease and adequate performance status who were stratified by prognostic score and geographical region and randomly assigned to receive either 3 mg/kg nivolumab and 1 mg/kg ipilimumab every 3 weeks for four doses, then 3 mg/kg nivolumab monotherapy every other week, or 50 mg oral sunitinib once daily for 4 weeks in a 6-week cycle. Treatment continued until patients progressed or experienced unacceptable toxicity.
Most of the patients in the study (847 of 1,096) had intermediate- to poor-risk disease and most of those (about 70%) were PD-L1 negative.
Overall, the study met two of the primary endpoints, demonstrating superior overall survival and overall response rates with nivo/ipi vs. sunitinib in intermediate/poor-risk patients with treatment-naive advanced renal cell carcinoma, Dr. Motzer said.
In addition to presenting the subgroup data regarding outcomes across PD-L1 expression levels at the meeting, he also presented new data showing improved self-reported quality of life among patients treated with nivo/ipi vs. sunitinib. Quality of life was measured using the National Comprehensive Cancer Network/ Functional Assessment Of Cancer Therapy–Kidney Symptom Index 19 questionnaire, which “looks at questions particularly relevant to renal cell carcinoma patients,” he said.
The mean change in questionnaire scores from baseline was consistently better in the nivo/ipi arm. At 104 weeks the mean change was about +5 points with nivo/ipi vs. about –7 points with sunitinib.
“These results support the use of nivo/ipi as a new first-line standard of care option for patients with intermediate/poor-risk advanced [renal cell carcinoma],” he concluded.
CheckMate 214 was funded by Bristol-Myers Squibb and Ono Pharmaceutical. Dr. Motzer reported ownership interest in Armo Biosciences.
AT SITC 2017
Key clinical point:
Major finding: Overall response outcomes favored nivo/ipi vs. sunitinib for both PD-L1–positive tumors and PD-L1–negative tumors, but more so for PD-L1–positive tumors (P less than .0001 and P = .252, respectively).
Data source: The 1,096-patient open-label, phase 3 CheckMate 214 trial.
Disclosures: CheckMate 214 was funded by Bristol-Myers Squibb and Ono Pharmaceutical.
Neoantigen profiling predicts response to immunotherapy
In antitumor immunity and immunotherapy, quality and fitness count.
Specifically, the quality and fitness of neoantigens – tumor-specific mutated peptides on the surface of cancer cells – can influence a patient’s response to immune checkpoint inhibitors, and mathematical models of neoantigen fitness can serve as biomarkers for response to immunotherapy, according to investigators of two separate but related studies published in Nature.
In one study, Marta Łuksza, PhD, from the Simons Center for Systems Biology at the Institute for Advanced Study in Princeton, N.J., and colleagues propose a neoantigen fitness model that can predict tumor response to checkpoint blockade immunotherapy.
Importantly, low-fitness neoantigens identified by our method may be leveraged for developing novel immunotherapies,” they wrote (Nature. 2017 Nov 8. doi: 10.1038/nature24473).
In a related study, Vinod P. Balachandran, MD, from the David M. Rubinstein Center for Pancreatic Cancer Research at Memorial Sloan Kettering Cancer Center in New York and colleagues, including Dr. Łuksza and others, looked at T-cell antigens in long-term survivors of pancreatic cancer and identified specific neoantigens as T-cell targets.
“More broadly, we identify neoantigen quality as a biomarker for immunogenic tumors that may guide the application of immunotherapies,” Dr. Balachandran and colleagues wrote (Nature. 2017 Nov 8. doi: 10.1038/nature24462).
Proof of concept
The studies provide a proof of concept that mathematical modeling of tumor evolution and the interactions of tumors with the immune system may soon provide clinicians with valuable and actionable information about responses to immunotherapy, Benjamin Greenbaum, PhD, senior author on the study by Łuksza et al., and a coauthor on the pancreatic cancer study said in an interview.
“We’re trying to come up with measures that take into account what we think the underlying processes are and what lies behind therapy response, and that should lead to better predictive models associated with response in the future,” said Dr. Greenbaum, of the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai Medical Center, New York.
One of the key findings of the studies is that neoantigen quality – the ability of neoantigens to spark T-cell recognition – seems to be as or more important than neoantigen quantity for influencing immune responses during tumor evolution.
“The general logic behind the idea that mutational burden can be a good predictor of response is that the more mutations you have, the more likely that you have a neoantigen, a peptide generated by a tumor mutation, that elicits productive T-cell recognition. We tried to model that process that might lead to productive T-cell recognition, to assign a kind of number to every neoantigen to provide some estimate of how likely it was to undergo a productive process,” Dr. Greenbaum explained.
Melanoma and lung cancer survivors
In the study by Łuksza et al., the investigators created a mathematical fitness model that can predict how tumors respond to immunotherapy based on how neoantigens interact with the immune system and applied the model to data on three previously reported patient cohorts, including two groups of patients with malignant melanoma treated with a cytotoxic T-lymphocyte associated protein 4 (CTLA4) immune checkpoint such as ipilimumab (Yervoy), and one group of patients with non–small cell lung cancer treated with a programmed death-1 (PD-1) inhibitor (for example, nivolumab [Opdivo]).
They found that their proposed model is more accurate than genomic biomarkers for predicting how a specific tumor may respond to immunotherapy.
“Importantly, low-fitness neoantigens identified by our method may be leveraged for developing novel immunotherapies. By using an immune fitness model to study immunotherapy, we reveal broad similarities between the evolution of tumors and rapidly evolving pathogens,” they wrote.
Pancreatic cancer survivors
Fewer than 7% of patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) survive more than 5 years, despite the best surgical and medical therapy. But a few lucky patients are long-term survivors, and Dr. Balachandran and associates sought to examine what aspects of T-cell immunity contributed to their longevity.
Rather than relying on genomic analysis of tumor samples, however, they used a combination of genetic, immunohistochemical, and transcriptional immunoprofiling, as well as computational biophysics and function to identify T-cell antigens in the long-term survivors.
When they compared surgically resected patients matched by tumor stage, they found that tumors from those with a median overall survival (OS) of 6 years had a 3-fold greater density of CD8-positive T cells and a 12-fold greater density of cytolytic CD8-positive cells, as well as more mature dendritic cells, regulatory T cells, and macrophages, but decreased numbers of CD4-positive T cells, compared with patients with a more typical course of survival (median OS, 0.8 years). There were no differences between long- and short-term survivors in either B cells or major histocompatibility complex (MHC) class I–positive cells.
They then performed whole-exome sequencing on tumor samples to determine the frequency of neoantigens and found a median of 38 predicted neoantigens per tumor.
“Notably, patients with both the highest predicted neoantigen number and either the greatest CD3+, CD8+, or polyclonal T-cell repertoire, but neither alone, exhibited the longest survival,” they wrote.
When they looked for qualities of neoantigens responsible for promoting T-cell activation in the long-term survivors, they found that the tumors from the survivors, compared with others, were enriched in neoantigen qualities that could be described by a mathematical fitness model.
“Our results provide insight into the heterogeneous immunobiology of PDAC, a presumed poorly immunogenic and checkpoint blockade–refractory tumor, demonstrating that neoantigens may be T-cell targets in [long-term survivors]”, they wrote.
The investigators propose that immunity to neoantigens that are generated during the outgrowth of a primary tumor could at least partially explain the lower incidence of relapse and prolonged survival of a small minority of patients with pancreatic cancer.
“Our findings support the development of strategies to harness neoantigen-specific immunity to treat checkpoint blockade–refractory cancers, and the identification of immunogenic hot spots for directed neoantigen targeting,” they concluded.
The studies were supported by grants from Stand Up to Cancer, American Cancer Society, National Science Foundation, Lustgarten Foundation, Janssen Research & Development, the STARR Cancer Consortium, the Pershing Square Sohn Cancer Research Alliance, the National Institutes of Health, the V Foundation, Swim Across America, Ludwig Institute for Cancer Research, the Parker Institute for Cancer Immunotherapy, a National Cancer Institute Career Development Award, and a Memorial Sloan Kettering Cancer Center core grant. Dr. Łuksza and Dr. Greenbaum disclosed consulting for Merck. Dr. Balachandran disclosed research funding from Bristol-Myers Squibb.
In antitumor immunity and immunotherapy, quality and fitness count.
Specifically, the quality and fitness of neoantigens – tumor-specific mutated peptides on the surface of cancer cells – can influence a patient’s response to immune checkpoint inhibitors, and mathematical models of neoantigen fitness can serve as biomarkers for response to immunotherapy, according to investigators of two separate but related studies published in Nature.
In one study, Marta Łuksza, PhD, from the Simons Center for Systems Biology at the Institute for Advanced Study in Princeton, N.J., and colleagues propose a neoantigen fitness model that can predict tumor response to checkpoint blockade immunotherapy.
Importantly, low-fitness neoantigens identified by our method may be leveraged for developing novel immunotherapies,” they wrote (Nature. 2017 Nov 8. doi: 10.1038/nature24473).
In a related study, Vinod P. Balachandran, MD, from the David M. Rubinstein Center for Pancreatic Cancer Research at Memorial Sloan Kettering Cancer Center in New York and colleagues, including Dr. Łuksza and others, looked at T-cell antigens in long-term survivors of pancreatic cancer and identified specific neoantigens as T-cell targets.
“More broadly, we identify neoantigen quality as a biomarker for immunogenic tumors that may guide the application of immunotherapies,” Dr. Balachandran and colleagues wrote (Nature. 2017 Nov 8. doi: 10.1038/nature24462).
Proof of concept
The studies provide a proof of concept that mathematical modeling of tumor evolution and the interactions of tumors with the immune system may soon provide clinicians with valuable and actionable information about responses to immunotherapy, Benjamin Greenbaum, PhD, senior author on the study by Łuksza et al., and a coauthor on the pancreatic cancer study said in an interview.
“We’re trying to come up with measures that take into account what we think the underlying processes are and what lies behind therapy response, and that should lead to better predictive models associated with response in the future,” said Dr. Greenbaum, of the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai Medical Center, New York.
One of the key findings of the studies is that neoantigen quality – the ability of neoantigens to spark T-cell recognition – seems to be as or more important than neoantigen quantity for influencing immune responses during tumor evolution.
“The general logic behind the idea that mutational burden can be a good predictor of response is that the more mutations you have, the more likely that you have a neoantigen, a peptide generated by a tumor mutation, that elicits productive T-cell recognition. We tried to model that process that might lead to productive T-cell recognition, to assign a kind of number to every neoantigen to provide some estimate of how likely it was to undergo a productive process,” Dr. Greenbaum explained.
Melanoma and lung cancer survivors
In the study by Łuksza et al., the investigators created a mathematical fitness model that can predict how tumors respond to immunotherapy based on how neoantigens interact with the immune system and applied the model to data on three previously reported patient cohorts, including two groups of patients with malignant melanoma treated with a cytotoxic T-lymphocyte associated protein 4 (CTLA4) immune checkpoint such as ipilimumab (Yervoy), and one group of patients with non–small cell lung cancer treated with a programmed death-1 (PD-1) inhibitor (for example, nivolumab [Opdivo]).
They found that their proposed model is more accurate than genomic biomarkers for predicting how a specific tumor may respond to immunotherapy.
“Importantly, low-fitness neoantigens identified by our method may be leveraged for developing novel immunotherapies. By using an immune fitness model to study immunotherapy, we reveal broad similarities between the evolution of tumors and rapidly evolving pathogens,” they wrote.
Pancreatic cancer survivors
Fewer than 7% of patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) survive more than 5 years, despite the best surgical and medical therapy. But a few lucky patients are long-term survivors, and Dr. Balachandran and associates sought to examine what aspects of T-cell immunity contributed to their longevity.
Rather than relying on genomic analysis of tumor samples, however, they used a combination of genetic, immunohistochemical, and transcriptional immunoprofiling, as well as computational biophysics and function to identify T-cell antigens in the long-term survivors.
When they compared surgically resected patients matched by tumor stage, they found that tumors from those with a median overall survival (OS) of 6 years had a 3-fold greater density of CD8-positive T cells and a 12-fold greater density of cytolytic CD8-positive cells, as well as more mature dendritic cells, regulatory T cells, and macrophages, but decreased numbers of CD4-positive T cells, compared with patients with a more typical course of survival (median OS, 0.8 years). There were no differences between long- and short-term survivors in either B cells or major histocompatibility complex (MHC) class I–positive cells.
They then performed whole-exome sequencing on tumor samples to determine the frequency of neoantigens and found a median of 38 predicted neoantigens per tumor.
“Notably, patients with both the highest predicted neoantigen number and either the greatest CD3+, CD8+, or polyclonal T-cell repertoire, but neither alone, exhibited the longest survival,” they wrote.
When they looked for qualities of neoantigens responsible for promoting T-cell activation in the long-term survivors, they found that the tumors from the survivors, compared with others, were enriched in neoantigen qualities that could be described by a mathematical fitness model.
“Our results provide insight into the heterogeneous immunobiology of PDAC, a presumed poorly immunogenic and checkpoint blockade–refractory tumor, demonstrating that neoantigens may be T-cell targets in [long-term survivors]”, they wrote.
The investigators propose that immunity to neoantigens that are generated during the outgrowth of a primary tumor could at least partially explain the lower incidence of relapse and prolonged survival of a small minority of patients with pancreatic cancer.
“Our findings support the development of strategies to harness neoantigen-specific immunity to treat checkpoint blockade–refractory cancers, and the identification of immunogenic hot spots for directed neoantigen targeting,” they concluded.
The studies were supported by grants from Stand Up to Cancer, American Cancer Society, National Science Foundation, Lustgarten Foundation, Janssen Research & Development, the STARR Cancer Consortium, the Pershing Square Sohn Cancer Research Alliance, the National Institutes of Health, the V Foundation, Swim Across America, Ludwig Institute for Cancer Research, the Parker Institute for Cancer Immunotherapy, a National Cancer Institute Career Development Award, and a Memorial Sloan Kettering Cancer Center core grant. Dr. Łuksza and Dr. Greenbaum disclosed consulting for Merck. Dr. Balachandran disclosed research funding from Bristol-Myers Squibb.
In antitumor immunity and immunotherapy, quality and fitness count.
Specifically, the quality and fitness of neoantigens – tumor-specific mutated peptides on the surface of cancer cells – can influence a patient’s response to immune checkpoint inhibitors, and mathematical models of neoantigen fitness can serve as biomarkers for response to immunotherapy, according to investigators of two separate but related studies published in Nature.
In one study, Marta Łuksza, PhD, from the Simons Center for Systems Biology at the Institute for Advanced Study in Princeton, N.J., and colleagues propose a neoantigen fitness model that can predict tumor response to checkpoint blockade immunotherapy.
Importantly, low-fitness neoantigens identified by our method may be leveraged for developing novel immunotherapies,” they wrote (Nature. 2017 Nov 8. doi: 10.1038/nature24473).
In a related study, Vinod P. Balachandran, MD, from the David M. Rubinstein Center for Pancreatic Cancer Research at Memorial Sloan Kettering Cancer Center in New York and colleagues, including Dr. Łuksza and others, looked at T-cell antigens in long-term survivors of pancreatic cancer and identified specific neoantigens as T-cell targets.
“More broadly, we identify neoantigen quality as a biomarker for immunogenic tumors that may guide the application of immunotherapies,” Dr. Balachandran and colleagues wrote (Nature. 2017 Nov 8. doi: 10.1038/nature24462).
Proof of concept
The studies provide a proof of concept that mathematical modeling of tumor evolution and the interactions of tumors with the immune system may soon provide clinicians with valuable and actionable information about responses to immunotherapy, Benjamin Greenbaum, PhD, senior author on the study by Łuksza et al., and a coauthor on the pancreatic cancer study said in an interview.
“We’re trying to come up with measures that take into account what we think the underlying processes are and what lies behind therapy response, and that should lead to better predictive models associated with response in the future,” said Dr. Greenbaum, of the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai Medical Center, New York.
One of the key findings of the studies is that neoantigen quality – the ability of neoantigens to spark T-cell recognition – seems to be as or more important than neoantigen quantity for influencing immune responses during tumor evolution.
“The general logic behind the idea that mutational burden can be a good predictor of response is that the more mutations you have, the more likely that you have a neoantigen, a peptide generated by a tumor mutation, that elicits productive T-cell recognition. We tried to model that process that might lead to productive T-cell recognition, to assign a kind of number to every neoantigen to provide some estimate of how likely it was to undergo a productive process,” Dr. Greenbaum explained.
Melanoma and lung cancer survivors
In the study by Łuksza et al., the investigators created a mathematical fitness model that can predict how tumors respond to immunotherapy based on how neoantigens interact with the immune system and applied the model to data on three previously reported patient cohorts, including two groups of patients with malignant melanoma treated with a cytotoxic T-lymphocyte associated protein 4 (CTLA4) immune checkpoint such as ipilimumab (Yervoy), and one group of patients with non–small cell lung cancer treated with a programmed death-1 (PD-1) inhibitor (for example, nivolumab [Opdivo]).
They found that their proposed model is more accurate than genomic biomarkers for predicting how a specific tumor may respond to immunotherapy.
“Importantly, low-fitness neoantigens identified by our method may be leveraged for developing novel immunotherapies. By using an immune fitness model to study immunotherapy, we reveal broad similarities between the evolution of tumors and rapidly evolving pathogens,” they wrote.
Pancreatic cancer survivors
Fewer than 7% of patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) survive more than 5 years, despite the best surgical and medical therapy. But a few lucky patients are long-term survivors, and Dr. Balachandran and associates sought to examine what aspects of T-cell immunity contributed to their longevity.
Rather than relying on genomic analysis of tumor samples, however, they used a combination of genetic, immunohistochemical, and transcriptional immunoprofiling, as well as computational biophysics and function to identify T-cell antigens in the long-term survivors.
When they compared surgically resected patients matched by tumor stage, they found that tumors from those with a median overall survival (OS) of 6 years had a 3-fold greater density of CD8-positive T cells and a 12-fold greater density of cytolytic CD8-positive cells, as well as more mature dendritic cells, regulatory T cells, and macrophages, but decreased numbers of CD4-positive T cells, compared with patients with a more typical course of survival (median OS, 0.8 years). There were no differences between long- and short-term survivors in either B cells or major histocompatibility complex (MHC) class I–positive cells.
They then performed whole-exome sequencing on tumor samples to determine the frequency of neoantigens and found a median of 38 predicted neoantigens per tumor.
“Notably, patients with both the highest predicted neoantigen number and either the greatest CD3+, CD8+, or polyclonal T-cell repertoire, but neither alone, exhibited the longest survival,” they wrote.
When they looked for qualities of neoantigens responsible for promoting T-cell activation in the long-term survivors, they found that the tumors from the survivors, compared with others, were enriched in neoantigen qualities that could be described by a mathematical fitness model.
“Our results provide insight into the heterogeneous immunobiology of PDAC, a presumed poorly immunogenic and checkpoint blockade–refractory tumor, demonstrating that neoantigens may be T-cell targets in [long-term survivors]”, they wrote.
The investigators propose that immunity to neoantigens that are generated during the outgrowth of a primary tumor could at least partially explain the lower incidence of relapse and prolonged survival of a small minority of patients with pancreatic cancer.
“Our findings support the development of strategies to harness neoantigen-specific immunity to treat checkpoint blockade–refractory cancers, and the identification of immunogenic hot spots for directed neoantigen targeting,” they concluded.
The studies were supported by grants from Stand Up to Cancer, American Cancer Society, National Science Foundation, Lustgarten Foundation, Janssen Research & Development, the STARR Cancer Consortium, the Pershing Square Sohn Cancer Research Alliance, the National Institutes of Health, the V Foundation, Swim Across America, Ludwig Institute for Cancer Research, the Parker Institute for Cancer Immunotherapy, a National Cancer Institute Career Development Award, and a Memorial Sloan Kettering Cancer Center core grant. Dr. Łuksza and Dr. Greenbaum disclosed consulting for Merck. Dr. Balachandran disclosed research funding from Bristol-Myers Squibb.
FROM NATURE
Key clinical point: Proof-of-concept studies show that mathematical modeling of neoantigens can be used to predict tumor responses to immune checkpoint inhibitors.
Major finding: Neoantigen quality may be a better biomarker for guiding immunotherapy than tumor genomic profiling.
Data source: Basic science reports focusing on neoantigens and their potential influence on tumor interactions with the immune system.
Disclosures: The studies were supported by grants from Stand Up to Cancer, American Cancer Society, National Science Foundation, Lustgarten Foundation, Janssen Research & Development, the STARR Cancer Consortium, the Pershing Square Sohn Cancer Research Alliance, the National Institutes of Health, the V Foundation, Swim Across America, Ludwig Institute for Cancer Research, the Parker Institute for Cancer Immunotherapy, a National Cancer Institute Career Development Award, and a Memorial Sloan Kettering Cancer Center core grant. Dr. Łuksza and Dr. Greenbaum disclosed consulting for Merck. Dr. Balachandran disclosed research funding from Bristol-Myers Squibb.
Nivolumab linked to CNS disorder in case report
Autoimmune encephalitis may be a potentially severe complication of immune checkpoint inhibitor therapy, a case report suggests.
The recently published report describes a 53-year-old man with B-cell non-Hodgkin lymphoma who presented with double vision, ataxia, impaired speech, and mild cognitive dysfunction following treatment with the immune checkpoint inhibitor nivolumab.
Neuropathologic examination of a biopsied brain lesion found on cranial MRI showed a T cell–dominated inflammatory process thought to be autoimmune in origin, according to Herwig Strik, MD, of the department of neurology at Philipps University of Marburg (Germany), and his colleagues (Eur J Cancer. 2017 Oct 16. doi: 10.1016/j.ejca.2017.09.026).
After the patient stopped taking nivolumab and the inflammatory process was treated, his “clinical neurological and radiological status remained stable but disabling with fluctuating dysarthria and ataxia,” Dr. Strik and his colleagues wrote.
“Since these novel anticancer agents are increasingly used, this severe complication should be recognized soon and treatment should be terminated to avoid chronification,” they said in the report.
Nivolumab and other checkpoint inhibitors are known to have autoimmune side effects in some cases that can affect the pulmonary, gastrointestinal, and endocrine systems, the authors said.
Several previous case reports have detailed encephalitis occurring in cancer patients receiving nivolumab, the combination of nivolumab plus the immune checkpoint inhibitor ipilimumab, or ipilimumab alone. The authors said they believe that this case report is the first to describe multifocal CNS inflammation following nivolumab treatment for systemic lymphoma.
The patient was diagnosed with B-cell non-Hodgkin lymphoma in 2005, according to the case report. He was first treated in 2009 with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone), followed by stem cell apheresis, radioimmunotherapy, and rituximab; he then received R-DHAP (rituximab, dexamethasone, high-dose cytarabine, and cisplatin) in August 2014, followed by autologous stem cell transplantation in October of that year. The patient started nivolumab maintenance therapy in February 2015 but started experiencing neurological symptoms that eventually led to ending nivolumab treatment in September 2015.
The patient’s lymphoma relapsed in June 2016. “The disabling neurological symptoms and his personal situation, however, worsened the patient’s depressive symptoms so severely that he went abroad to commit assisted suicide,” wrote Dr. Strik and his colleagues.
The authors proposed the term “immune checkpoint inhibitor–associated CNS autoimmune disorder (ICICAD)” to describe the inflammatory condition described in the case report.
They declared no conflicts of interest related to the case report and did not receive grant support for conducting the research described in it.
Autoimmune encephalitis may be a potentially severe complication of immune checkpoint inhibitor therapy, a case report suggests.
The recently published report describes a 53-year-old man with B-cell non-Hodgkin lymphoma who presented with double vision, ataxia, impaired speech, and mild cognitive dysfunction following treatment with the immune checkpoint inhibitor nivolumab.
Neuropathologic examination of a biopsied brain lesion found on cranial MRI showed a T cell–dominated inflammatory process thought to be autoimmune in origin, according to Herwig Strik, MD, of the department of neurology at Philipps University of Marburg (Germany), and his colleagues (Eur J Cancer. 2017 Oct 16. doi: 10.1016/j.ejca.2017.09.026).
After the patient stopped taking nivolumab and the inflammatory process was treated, his “clinical neurological and radiological status remained stable but disabling with fluctuating dysarthria and ataxia,” Dr. Strik and his colleagues wrote.
“Since these novel anticancer agents are increasingly used, this severe complication should be recognized soon and treatment should be terminated to avoid chronification,” they said in the report.
Nivolumab and other checkpoint inhibitors are known to have autoimmune side effects in some cases that can affect the pulmonary, gastrointestinal, and endocrine systems, the authors said.
Several previous case reports have detailed encephalitis occurring in cancer patients receiving nivolumab, the combination of nivolumab plus the immune checkpoint inhibitor ipilimumab, or ipilimumab alone. The authors said they believe that this case report is the first to describe multifocal CNS inflammation following nivolumab treatment for systemic lymphoma.
The patient was diagnosed with B-cell non-Hodgkin lymphoma in 2005, according to the case report. He was first treated in 2009 with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone), followed by stem cell apheresis, radioimmunotherapy, and rituximab; he then received R-DHAP (rituximab, dexamethasone, high-dose cytarabine, and cisplatin) in August 2014, followed by autologous stem cell transplantation in October of that year. The patient started nivolumab maintenance therapy in February 2015 but started experiencing neurological symptoms that eventually led to ending nivolumab treatment in September 2015.
The patient’s lymphoma relapsed in June 2016. “The disabling neurological symptoms and his personal situation, however, worsened the patient’s depressive symptoms so severely that he went abroad to commit assisted suicide,” wrote Dr. Strik and his colleagues.
The authors proposed the term “immune checkpoint inhibitor–associated CNS autoimmune disorder (ICICAD)” to describe the inflammatory condition described in the case report.
They declared no conflicts of interest related to the case report and did not receive grant support for conducting the research described in it.
Autoimmune encephalitis may be a potentially severe complication of immune checkpoint inhibitor therapy, a case report suggests.
The recently published report describes a 53-year-old man with B-cell non-Hodgkin lymphoma who presented with double vision, ataxia, impaired speech, and mild cognitive dysfunction following treatment with the immune checkpoint inhibitor nivolumab.
Neuropathologic examination of a biopsied brain lesion found on cranial MRI showed a T cell–dominated inflammatory process thought to be autoimmune in origin, according to Herwig Strik, MD, of the department of neurology at Philipps University of Marburg (Germany), and his colleagues (Eur J Cancer. 2017 Oct 16. doi: 10.1016/j.ejca.2017.09.026).
After the patient stopped taking nivolumab and the inflammatory process was treated, his “clinical neurological and radiological status remained stable but disabling with fluctuating dysarthria and ataxia,” Dr. Strik and his colleagues wrote.
“Since these novel anticancer agents are increasingly used, this severe complication should be recognized soon and treatment should be terminated to avoid chronification,” they said in the report.
Nivolumab and other checkpoint inhibitors are known to have autoimmune side effects in some cases that can affect the pulmonary, gastrointestinal, and endocrine systems, the authors said.
Several previous case reports have detailed encephalitis occurring in cancer patients receiving nivolumab, the combination of nivolumab plus the immune checkpoint inhibitor ipilimumab, or ipilimumab alone. The authors said they believe that this case report is the first to describe multifocal CNS inflammation following nivolumab treatment for systemic lymphoma.
The patient was diagnosed with B-cell non-Hodgkin lymphoma in 2005, according to the case report. He was first treated in 2009 with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone), followed by stem cell apheresis, radioimmunotherapy, and rituximab; he then received R-DHAP (rituximab, dexamethasone, high-dose cytarabine, and cisplatin) in August 2014, followed by autologous stem cell transplantation in October of that year. The patient started nivolumab maintenance therapy in February 2015 but started experiencing neurological symptoms that eventually led to ending nivolumab treatment in September 2015.
The patient’s lymphoma relapsed in June 2016. “The disabling neurological symptoms and his personal situation, however, worsened the patient’s depressive symptoms so severely that he went abroad to commit assisted suicide,” wrote Dr. Strik and his colleagues.
The authors proposed the term “immune checkpoint inhibitor–associated CNS autoimmune disorder (ICICAD)” to describe the inflammatory condition described in the case report.
They declared no conflicts of interest related to the case report and did not receive grant support for conducting the research described in it.
FROM THE EUROPEAN JOURNAL OF CANCER
Key clinical point: Autoimmune encephalitis may be a potential complication of checkpoint inhibitor therapy.
Major finding: A patient with B-cell non-Hodgkin lymphoma presented with double vision, ataxia, impaired speech, and mild cognitive dysfunction following treatment with nivolumab. Examination of a brain lesion showed a T cell–dominated inflammatory process thought to be autoimmune in origin.
Data source: A case report of a 53-year-old man with B-cell non-Hodgkin lymphoma (B-NHL) who received nivolumab maintenance treatment.
Disclosures: The authors declared no conflicts of interest and did not receive grant support for the research.
FDA approves second CAR-T therapy
A second chimeric antigen receptor (CAR) T-cell therapy has gained FDA approval, this time for the treatment of large B-cell lymphoma in adults.
“Today marks another milestone in the development of a whole new scientific paradigm for the treatment of serious diseases,” FDA Commissioner Scott Gottlieb, MD, said in a statement. “This approval demonstrates the continued momentum of this promising new area of medicine, and we’re committed to supporting and helping expedite the development of these products.”
Approval was based on ZUMA-1, a multicenter clinical trial of 101 adults with refractory or relapsed large B-cell lymphoma. Almost three-quarters (72%) of patients responded, including 51% who achieved complete remission.
CAR-T therapy can cause severe, life-threatening side effects, most notably cytokine release syndrome (CRS) and neurologic toxicities, for which axicabtagene ciloleucel will carry a boxed warning and will come with a risk evaluation and mitigation strategy (REMS), according to the FDA.
The list price for a single treatment of axicabtagene ciloleucel is $373,000, according to the manufacturer.
“We will soon release a comprehensive policy to address how we plan to support the development of cell-based regenerative medicine,” Dr. Gottlieb said in a statement. “That policy will also clarify how we will apply our expedited programs to breakthrough products that use CAR-T cells and other gene therapies. We remain committed to supporting the efficient development of safe and effective treatments that leverage these new scientific platforms.”
Axicabtagene ciloleucel was developed by Kite Pharma, which was acquired recently by Gilead Sciences.
[email protected]
On Twitter @denisefulton
A second chimeric antigen receptor (CAR) T-cell therapy has gained FDA approval, this time for the treatment of large B-cell lymphoma in adults.
“Today marks another milestone in the development of a whole new scientific paradigm for the treatment of serious diseases,” FDA Commissioner Scott Gottlieb, MD, said in a statement. “This approval demonstrates the continued momentum of this promising new area of medicine, and we’re committed to supporting and helping expedite the development of these products.”
Approval was based on ZUMA-1, a multicenter clinical trial of 101 adults with refractory or relapsed large B-cell lymphoma. Almost three-quarters (72%) of patients responded, including 51% who achieved complete remission.
CAR-T therapy can cause severe, life-threatening side effects, most notably cytokine release syndrome (CRS) and neurologic toxicities, for which axicabtagene ciloleucel will carry a boxed warning and will come with a risk evaluation and mitigation strategy (REMS), according to the FDA.
The list price for a single treatment of axicabtagene ciloleucel is $373,000, according to the manufacturer.
“We will soon release a comprehensive policy to address how we plan to support the development of cell-based regenerative medicine,” Dr. Gottlieb said in a statement. “That policy will also clarify how we will apply our expedited programs to breakthrough products that use CAR-T cells and other gene therapies. We remain committed to supporting the efficient development of safe and effective treatments that leverage these new scientific platforms.”
Axicabtagene ciloleucel was developed by Kite Pharma, which was acquired recently by Gilead Sciences.
[email protected]
On Twitter @denisefulton
A second chimeric antigen receptor (CAR) T-cell therapy has gained FDA approval, this time for the treatment of large B-cell lymphoma in adults.
“Today marks another milestone in the development of a whole new scientific paradigm for the treatment of serious diseases,” FDA Commissioner Scott Gottlieb, MD, said in a statement. “This approval demonstrates the continued momentum of this promising new area of medicine, and we’re committed to supporting and helping expedite the development of these products.”
Approval was based on ZUMA-1, a multicenter clinical trial of 101 adults with refractory or relapsed large B-cell lymphoma. Almost three-quarters (72%) of patients responded, including 51% who achieved complete remission.
CAR-T therapy can cause severe, life-threatening side effects, most notably cytokine release syndrome (CRS) and neurologic toxicities, for which axicabtagene ciloleucel will carry a boxed warning and will come with a risk evaluation and mitigation strategy (REMS), according to the FDA.
The list price for a single treatment of axicabtagene ciloleucel is $373,000, according to the manufacturer.
“We will soon release a comprehensive policy to address how we plan to support the development of cell-based regenerative medicine,” Dr. Gottlieb said in a statement. “That policy will also clarify how we will apply our expedited programs to breakthrough products that use CAR-T cells and other gene therapies. We remain committed to supporting the efficient development of safe and effective treatments that leverage these new scientific platforms.”
Axicabtagene ciloleucel was developed by Kite Pharma, which was acquired recently by Gilead Sciences.
[email protected]
On Twitter @denisefulton
Keynote 040: Pembrolizumab misses efficacy endpoint in advanced HNSCC
MADRID – Although pembrolizumab (Keytruda) was associated with a 19% reduction in the risk of death compared with the standard of care in patients with relapsed or metastatic head and neck squamous cell carcinoma (HNSCC) in the KEYNOTE 040 trial, the immune checkpoint inhibitor just missed meeting its primary efficacy endpoint of an improvement in overall survival.
The fault may lie in the confounding of overall survival results when patients who were initially assigned to standard of care were crossed over to subsequent therapy with a checkpoint inhibitor after the study ended, said lead investigator Ezra Cohen, MD, of Moores Cancer Center at UC San Diego Health Sciences in La Jolla, Calif.
“This was a trial that clearly did not meet its primary endpoint, but was felt to confer some benefit – at least in the opinion of this investigator – to pembrolizumab vs. standard of care,” he said at the European Society for Medical Oncology Congress.
The byzantine statistical design of the trial, while it may warm a mathematician’s heart, imposed stringent restrictions on the data that may also have led to the ultimate failure of the programmed death-1 (PD-1) inhibitor to meet the efficacy endpoint, he said.
In July 2017, Merck, which markets pembrolizumab, announced the failure in a press release, promising to present the data in a future medical meeting. Dr. Cohen’s ESMO presentation was the fulfillment of that promise.
In the trial, patients with squamous cell carcinomas of the oral cavity, oropharynx, hypopharynx, or larynx with disease progression after a platinum-containing chemotherapy regimen, or recurrence/disease progress within 3-6 months of multimodal therapy using platinum, were randomly assigned to therapy with either pembrolizumab 200 mg intravenously every 3 weeks for 2 years, or to standard of care at the investigator’s choice: either methotrexate 40 mg/m2 weekly, docetaxel 75 mg/m2 every 3 weeks, or cetuximab (Erbitux) 250 mg/m2 weekly after a loading dose of 400 mg per m2.
Some math required
Dr. Cohen explained that the statistical design of the trial involved a multiplicity strategy using a family-wise alpha strictly controlled at 0.025. The alpha was allocated in a stepwise fashion. The study hypothesis was that pembrolizumab would have an overall survival (OS) advantage with a one-side alpha, and if that was met, OS would then be looked at in specific cohorts according to expression of the PD ligand 1 (PD-L1) on cells, followed by evaluation of objective response rates and progression-free survival in each subgroup.
The final analysis was to be performed after 380 OS events had occurred among 495 randomized patients. The prespecified efficacy boundary for OS in the intention-to-treat (ITT) population was .0175, translating into a hazard ratio (HR) of 0.80.
Median OS in the ITT population was 8.4 months for the pembrolizumab arm, compared with 7.1 months for the standard-of-care arm. This translated into an HR of 0.81 (P = .0204), which do not reach the aforementioned efficacy boundary.
Rates of 1-year overall survival were 37% in the experimental arm, vs. 27% in the standard-of-care arm.
“When one looks at the biomarker-specific cohorts, we can see that these differences are further exaggerated in favor of pembrolizumab, Dr. Cohen said.
An analysis stratified by patients with PD-L1 expression on 1% or more of cells vs. less than 1% showed median overall OS of 8.7 months for those with higher levels of expression, vs. 7.1 months for expression levels below 1% (HR 0.75, P = .0078).
Similarly, an analysis comparing patients with a tumor proportion score (TPS; expression of PD-L1 in the membranes of 50% or more of tumor cells) with patients whose tumors had lower TPS levels showed a median OS of 11.6 months with pembrolizumab, vs. 7.9 months with standard of care (HR 0.54, P = .0017).
Objective response rates were also significantly higher with pembrolizumab in the patients with higher levels of both overall PD-L1 expression (17.3% vs. 9.9% with standard care), and in patients with 50% or more of tumor cells expressing membrane PD-L1 (26.6% vs. 65%, P = .0009).
In an exploratory analysis, the investigators also found that among patients in the standard of care arm who went on to receive a checkpoint inhibitor as subsequent therapy, the median OS was 20.1 months, compared with 9.8 months for patients who received other subsequent therapies, and 4.8 months for those who did not receive subsequent therapy, suggesting that crossover to a checkpoint inhibitor may have diluted overall survival differences between the trial arms, Dr. Cohen said.
Treatment-related adverse events of any grade were more frequent in the standard of care arm, except for hypothyroidism, which was substantially more frequent with pembrolizumab. The incidence of immune-mediated adverse events other than hypothyroidism was generally similar between the treatment arms.
“I think pembrolizumab, despite not meeting the primary endpoint of overall survival, showed evidence of activity and a [good] safety profile. So I think this study is borderline possible, since there is a 19% reduction in the risk of death, with a hazard ratio borderline to the statistical hypothesis that was initially planned,” said invited discussant Sandrine Faivre, MD, PhD, of Bichat-Beaujon University Hospitals in Paris.
Although pembrolizumab did not reach the primary efficacy endpoint in the ITT population, among patients with TPS of 50% or greater, the benefit with the PD-1 inhibitor was “exquisite” she said, adding that this subgroup of patients made up only 26% of the ITT population.
The study was funded by Merck. Dr. Cohen disclosed stock ownership in Human Longevity, Inc, and being an advisory board member for AstraZeneca, Bristol-Myers Squibb, Human Longevity, Merck, and Pfizer. Dr. Faivre disclosed unspecified relationships with Bayer Pharma, Bristol-Myers Squibb, Eli Lilly, Ipsen, Merck, Serono, and Novartis.
MADRID – Although pembrolizumab (Keytruda) was associated with a 19% reduction in the risk of death compared with the standard of care in patients with relapsed or metastatic head and neck squamous cell carcinoma (HNSCC) in the KEYNOTE 040 trial, the immune checkpoint inhibitor just missed meeting its primary efficacy endpoint of an improvement in overall survival.
The fault may lie in the confounding of overall survival results when patients who were initially assigned to standard of care were crossed over to subsequent therapy with a checkpoint inhibitor after the study ended, said lead investigator Ezra Cohen, MD, of Moores Cancer Center at UC San Diego Health Sciences in La Jolla, Calif.
“This was a trial that clearly did not meet its primary endpoint, but was felt to confer some benefit – at least in the opinion of this investigator – to pembrolizumab vs. standard of care,” he said at the European Society for Medical Oncology Congress.
The byzantine statistical design of the trial, while it may warm a mathematician’s heart, imposed stringent restrictions on the data that may also have led to the ultimate failure of the programmed death-1 (PD-1) inhibitor to meet the efficacy endpoint, he said.
In July 2017, Merck, which markets pembrolizumab, announced the failure in a press release, promising to present the data in a future medical meeting. Dr. Cohen’s ESMO presentation was the fulfillment of that promise.
In the trial, patients with squamous cell carcinomas of the oral cavity, oropharynx, hypopharynx, or larynx with disease progression after a platinum-containing chemotherapy regimen, or recurrence/disease progress within 3-6 months of multimodal therapy using platinum, were randomly assigned to therapy with either pembrolizumab 200 mg intravenously every 3 weeks for 2 years, or to standard of care at the investigator’s choice: either methotrexate 40 mg/m2 weekly, docetaxel 75 mg/m2 every 3 weeks, or cetuximab (Erbitux) 250 mg/m2 weekly after a loading dose of 400 mg per m2.
Some math required
Dr. Cohen explained that the statistical design of the trial involved a multiplicity strategy using a family-wise alpha strictly controlled at 0.025. The alpha was allocated in a stepwise fashion. The study hypothesis was that pembrolizumab would have an overall survival (OS) advantage with a one-side alpha, and if that was met, OS would then be looked at in specific cohorts according to expression of the PD ligand 1 (PD-L1) on cells, followed by evaluation of objective response rates and progression-free survival in each subgroup.
The final analysis was to be performed after 380 OS events had occurred among 495 randomized patients. The prespecified efficacy boundary for OS in the intention-to-treat (ITT) population was .0175, translating into a hazard ratio (HR) of 0.80.
Median OS in the ITT population was 8.4 months for the pembrolizumab arm, compared with 7.1 months for the standard-of-care arm. This translated into an HR of 0.81 (P = .0204), which do not reach the aforementioned efficacy boundary.
Rates of 1-year overall survival were 37% in the experimental arm, vs. 27% in the standard-of-care arm.
“When one looks at the biomarker-specific cohorts, we can see that these differences are further exaggerated in favor of pembrolizumab, Dr. Cohen said.
An analysis stratified by patients with PD-L1 expression on 1% or more of cells vs. less than 1% showed median overall OS of 8.7 months for those with higher levels of expression, vs. 7.1 months for expression levels below 1% (HR 0.75, P = .0078).
Similarly, an analysis comparing patients with a tumor proportion score (TPS; expression of PD-L1 in the membranes of 50% or more of tumor cells) with patients whose tumors had lower TPS levels showed a median OS of 11.6 months with pembrolizumab, vs. 7.9 months with standard of care (HR 0.54, P = .0017).
Objective response rates were also significantly higher with pembrolizumab in the patients with higher levels of both overall PD-L1 expression (17.3% vs. 9.9% with standard care), and in patients with 50% or more of tumor cells expressing membrane PD-L1 (26.6% vs. 65%, P = .0009).
In an exploratory analysis, the investigators also found that among patients in the standard of care arm who went on to receive a checkpoint inhibitor as subsequent therapy, the median OS was 20.1 months, compared with 9.8 months for patients who received other subsequent therapies, and 4.8 months for those who did not receive subsequent therapy, suggesting that crossover to a checkpoint inhibitor may have diluted overall survival differences between the trial arms, Dr. Cohen said.
Treatment-related adverse events of any grade were more frequent in the standard of care arm, except for hypothyroidism, which was substantially more frequent with pembrolizumab. The incidence of immune-mediated adverse events other than hypothyroidism was generally similar between the treatment arms.
“I think pembrolizumab, despite not meeting the primary endpoint of overall survival, showed evidence of activity and a [good] safety profile. So I think this study is borderline possible, since there is a 19% reduction in the risk of death, with a hazard ratio borderline to the statistical hypothesis that was initially planned,” said invited discussant Sandrine Faivre, MD, PhD, of Bichat-Beaujon University Hospitals in Paris.
Although pembrolizumab did not reach the primary efficacy endpoint in the ITT population, among patients with TPS of 50% or greater, the benefit with the PD-1 inhibitor was “exquisite” she said, adding that this subgroup of patients made up only 26% of the ITT population.
The study was funded by Merck. Dr. Cohen disclosed stock ownership in Human Longevity, Inc, and being an advisory board member for AstraZeneca, Bristol-Myers Squibb, Human Longevity, Merck, and Pfizer. Dr. Faivre disclosed unspecified relationships with Bayer Pharma, Bristol-Myers Squibb, Eli Lilly, Ipsen, Merck, Serono, and Novartis.
MADRID – Although pembrolizumab (Keytruda) was associated with a 19% reduction in the risk of death compared with the standard of care in patients with relapsed or metastatic head and neck squamous cell carcinoma (HNSCC) in the KEYNOTE 040 trial, the immune checkpoint inhibitor just missed meeting its primary efficacy endpoint of an improvement in overall survival.
The fault may lie in the confounding of overall survival results when patients who were initially assigned to standard of care were crossed over to subsequent therapy with a checkpoint inhibitor after the study ended, said lead investigator Ezra Cohen, MD, of Moores Cancer Center at UC San Diego Health Sciences in La Jolla, Calif.
“This was a trial that clearly did not meet its primary endpoint, but was felt to confer some benefit – at least in the opinion of this investigator – to pembrolizumab vs. standard of care,” he said at the European Society for Medical Oncology Congress.
The byzantine statistical design of the trial, while it may warm a mathematician’s heart, imposed stringent restrictions on the data that may also have led to the ultimate failure of the programmed death-1 (PD-1) inhibitor to meet the efficacy endpoint, he said.
In July 2017, Merck, which markets pembrolizumab, announced the failure in a press release, promising to present the data in a future medical meeting. Dr. Cohen’s ESMO presentation was the fulfillment of that promise.
In the trial, patients with squamous cell carcinomas of the oral cavity, oropharynx, hypopharynx, or larynx with disease progression after a platinum-containing chemotherapy regimen, or recurrence/disease progress within 3-6 months of multimodal therapy using platinum, were randomly assigned to therapy with either pembrolizumab 200 mg intravenously every 3 weeks for 2 years, or to standard of care at the investigator’s choice: either methotrexate 40 mg/m2 weekly, docetaxel 75 mg/m2 every 3 weeks, or cetuximab (Erbitux) 250 mg/m2 weekly after a loading dose of 400 mg per m2.
Some math required
Dr. Cohen explained that the statistical design of the trial involved a multiplicity strategy using a family-wise alpha strictly controlled at 0.025. The alpha was allocated in a stepwise fashion. The study hypothesis was that pembrolizumab would have an overall survival (OS) advantage with a one-side alpha, and if that was met, OS would then be looked at in specific cohorts according to expression of the PD ligand 1 (PD-L1) on cells, followed by evaluation of objective response rates and progression-free survival in each subgroup.
The final analysis was to be performed after 380 OS events had occurred among 495 randomized patients. The prespecified efficacy boundary for OS in the intention-to-treat (ITT) population was .0175, translating into a hazard ratio (HR) of 0.80.
Median OS in the ITT population was 8.4 months for the pembrolizumab arm, compared with 7.1 months for the standard-of-care arm. This translated into an HR of 0.81 (P = .0204), which do not reach the aforementioned efficacy boundary.
Rates of 1-year overall survival were 37% in the experimental arm, vs. 27% in the standard-of-care arm.
“When one looks at the biomarker-specific cohorts, we can see that these differences are further exaggerated in favor of pembrolizumab, Dr. Cohen said.
An analysis stratified by patients with PD-L1 expression on 1% or more of cells vs. less than 1% showed median overall OS of 8.7 months for those with higher levels of expression, vs. 7.1 months for expression levels below 1% (HR 0.75, P = .0078).
Similarly, an analysis comparing patients with a tumor proportion score (TPS; expression of PD-L1 in the membranes of 50% or more of tumor cells) with patients whose tumors had lower TPS levels showed a median OS of 11.6 months with pembrolizumab, vs. 7.9 months with standard of care (HR 0.54, P = .0017).
Objective response rates were also significantly higher with pembrolizumab in the patients with higher levels of both overall PD-L1 expression (17.3% vs. 9.9% with standard care), and in patients with 50% or more of tumor cells expressing membrane PD-L1 (26.6% vs. 65%, P = .0009).
In an exploratory analysis, the investigators also found that among patients in the standard of care arm who went on to receive a checkpoint inhibitor as subsequent therapy, the median OS was 20.1 months, compared with 9.8 months for patients who received other subsequent therapies, and 4.8 months for those who did not receive subsequent therapy, suggesting that crossover to a checkpoint inhibitor may have diluted overall survival differences between the trial arms, Dr. Cohen said.
Treatment-related adverse events of any grade were more frequent in the standard of care arm, except for hypothyroidism, which was substantially more frequent with pembrolizumab. The incidence of immune-mediated adverse events other than hypothyroidism was generally similar between the treatment arms.
“I think pembrolizumab, despite not meeting the primary endpoint of overall survival, showed evidence of activity and a [good] safety profile. So I think this study is borderline possible, since there is a 19% reduction in the risk of death, with a hazard ratio borderline to the statistical hypothesis that was initially planned,” said invited discussant Sandrine Faivre, MD, PhD, of Bichat-Beaujon University Hospitals in Paris.
Although pembrolizumab did not reach the primary efficacy endpoint in the ITT population, among patients with TPS of 50% or greater, the benefit with the PD-1 inhibitor was “exquisite” she said, adding that this subgroup of patients made up only 26% of the ITT population.
The study was funded by Merck. Dr. Cohen disclosed stock ownership in Human Longevity, Inc, and being an advisory board member for AstraZeneca, Bristol-Myers Squibb, Human Longevity, Merck, and Pfizer. Dr. Faivre disclosed unspecified relationships with Bayer Pharma, Bristol-Myers Squibb, Eli Lilly, Ipsen, Merck, Serono, and Novartis.
AT ESMO 2017
Key clinical point: Pembrolizumab was associated with a 19% reduction in the risk of death in patients with advanced HNSCC, but was not significantly better than standard of care.
Major finding: Median overall survival in the ITT population was 8.4 months with pembrolizumab arm, vs 7.1 months for the standard-of-care arm. The difference did not reach the prespecified efficacy boundary.
Data source: Randomized phase 3 trial of 495 patients with relapsed or metastatic head and neck squamous cell carcinoma.
Disclosures: Merck funded the study. Dr. Cohen disclosed stock ownership in Human Longevity, and being an advisory board member for AstraZeneca, Bristol-Myers Squibb, Human Longevity, Merck, and Pfizer. Dr. Faivre disclosed unspecified relationships with Bayer Pharma, Bristol-Myers Squibb, Eli Lilly, Ipsen, Merck, Serono, and Novartis.
Cascade of costs could push new gene therapy above $1 million per patient
Outrage over the high cost of cancer care has focused on skyrocketing drug prices, including the $475,000 price tag for the country’s first gene therapy, Novartis’ Kymriah (tisagenlecleucel), a leukemia treatment approved in August.
But the total costs of tisagenlecleucel and the 21 similar drugs in development – known as CAR T-cell therapies – will be far higher than many have imagined, reaching $1 million or more per patient, according to leading cancer experts. The next CAR T-cell drug could be approved as soon as November.
Although Kymriah’s price tag has “shattered oncology drug pricing norms,” said Leonard Saltz, MD, chief of gastrointestinal oncology at Memorial Sloan Kettering Cancer Center in New York, “the sticker price is just the starting point.”
These therapies lead to a cascade of costs, propelled by serious side effects that require sophisticated management, Dr. Saltz said. For this class of drugs, Dr, Saltz advised consumers to “think of the $475,000 as parts, not labor.”
Hagop Kantarjian, MD, leukemia specialist and professor at the University of Texas MD Anderson Cancer Center, estimates tisagenlecleucel’s total cost could reach $1.5 million.
CAR T-cell therapy is expensive because of the unique way that it works. Doctors harvest patients’ immune cells, genetically alter them to rev up their ability to fight cancer, then reinfuse them into patients.
Taking the brakes off the immune system, Dr. Kantarjian said, can lead to life-threatening complications that require lengthy hospitalizations and expensive medications, which are prescribed in addition to conventional cancer therapy, rather than in place of it.
Keith D. Eaton, MD, a Seattle oncologist, said he ran up medical bills of $500,000 when he participated in a clinical trial of CAR T cells in 2013, even though all patients in the study received the medication for free. Dr. Eaton, who was diagnosed with acute lymphoblastic leukemia (ALL), spent nearly 2 months in the hospital.
Like Dr. Eaton, nearly half of patients who receive CAR T cells develop cytokine storm. Other serious side effects include strokelike symptoms and coma.
The cytokine storm felt like “the worst flu of your life,” said Dr. Eaton, now aged 51 years. His fever spiked so high that a hospital nurse assumed the thermometer was broken. Dr. Eaton replied, “It’s not broken. My temperature is too high to register on the thermometer.”
Although Dr. Eaton recovered, he wasn’t done with treatment. His doctors recommended a bone marrow transplant, another harrowing procedure, at a cost of hundreds of thousands of dollars.
Dr. Eaton said he feels fortunate to be healthy today, with tests showing no evidence of leukemia. His insurer paid for almost everything.
Kymriah’s sticker price is especially “outrageous” given its relatively low manufacturing costs, said Walid F. Gellad, MD, codirector of the Center for Pharmaceutical Policy and Prescribing at the University of Pittsburgh.
The gene therapy process used to create tisagenlecleucel costs about $15,000, according to a 2012 presentation by Carl H. June, MD, who pioneered CAR T-cell research at the University of Pennsylvania in Philadelphia. Dr. June could not be reached for comment.
To quell unrest about price, Novartis has offered patients and insurers a new twist on the money-back guarantee.
Novartis will charge for the drug only if patients go into remission within 1 month of treatment. In a key clinical trial, 83% of the children and young adults treated with tisagenlecleucel went into remission within 3 months. Novartis calls the plan “outcomes-based pricing.”
Novartis is “working through the specific details” of how the pricing plan will affect the Centers for Medicare & Medicaid Services, which pays for care for many cancer patients, company spokesperson Julie Masow said. “There are many hurdles” to this type of pricing plan but, Ms. Masow said, “Novartis is committed to making this happen.”
She also said that Kymriah’s manufacturing costs are much higher than $15,000, although she didn’t cite a specific dollar amount. She noted that Novartis has invested heavily in the technology, designing “an innovative manufacturing facility and process specifically for cellular therapies.”
As for Kymriah-related hospital and medication charges, “costs will vary from patient to patient and treatment center to treatment center, based on the level of care each patient requires,” Ms. Masow said. “Kymriah is a one-time treatment that has shown remarkable early, deep, and durable responses in these children who are very sick and often out of options.”
Some doctors said tisagenlecleucel, which could be used by about 600 patients a year, offers an incalculable benefit for desperately ill young people. The drug is approved for children and young adults with B-cell ALL who already have been treated with at least two other cancer therapies.
“A kid’s life is priceless,” said Michelle Hermiston, MD, director of pediatric immunotherapy at Benioff Children’s Hospital, at the University of California, San Francisco. “Any given kid has the potential to make financial impacts over a lifetime that far outweigh the cost of their cure. From this perspective, every child in my mind deserves the best curative therapy we can offer.”
Other cancer doctors say the Novartis plan is no bargain.
About 36% of patients who go into remission with tisagenlecleucel relapse within 1 year, said Vinay Prasad, MD, of Oregon Health & Science University, Portland. Many of these patients will need additional treatment, said Dr. Prasad, who wrote an editorial about tisagenlecleucel’s price Oct. 4 in Nature.
“If you’ve paid half a million dollars for drugs and half a million dollars for care, and a year later your cancer is back, is that a good deal?” asked Dr. Saltz, who cowrote a recent editorial on tisagenlecleucel’s price in JAMA.
Steve Miller, MD, chief medical officer for Express Scripts, said it would be more fair to judge Kymriah’s success after 6 months of treatment, rather than 1 month. Dr. Prasad goes even further. He said Novartis should issue refunds for any patient who relapses within 3 years.
A consumer-advocate group called Patients for Affordable Drugs also has said that tisagenlecleucel costs too much, given that the federal government spent more than $200 million over 2 decades to support the basic research into CAR T-cell therapy, long before Novartis bought the rights.
Rep. Lloyd Doggett (D-Texas) wrote a letter to the Medicare program’s director last month asking for details on how the Novartis payment deal will work.
“As Big Pharma continues to put price gouging before patient access, companies will point more and more proudly at their pricing agreements,” Rep. Doggett wrote. “But taxpayers deserve to know more about how these agreements will work – whether they will actually save the government money, defray these massive costs, and ensure that they can access lifesaving medications.”
KHN’s coverage related to aging & improving care of older adults is supported by The John A. Hartford Foundation. Kaiser Health News is a national health policy news service that is part of the nonpartisan Henry J. Kaiser Family Foundation.
Outrage over the high cost of cancer care has focused on skyrocketing drug prices, including the $475,000 price tag for the country’s first gene therapy, Novartis’ Kymriah (tisagenlecleucel), a leukemia treatment approved in August.
But the total costs of tisagenlecleucel and the 21 similar drugs in development – known as CAR T-cell therapies – will be far higher than many have imagined, reaching $1 million or more per patient, according to leading cancer experts. The next CAR T-cell drug could be approved as soon as November.
Although Kymriah’s price tag has “shattered oncology drug pricing norms,” said Leonard Saltz, MD, chief of gastrointestinal oncology at Memorial Sloan Kettering Cancer Center in New York, “the sticker price is just the starting point.”
These therapies lead to a cascade of costs, propelled by serious side effects that require sophisticated management, Dr. Saltz said. For this class of drugs, Dr, Saltz advised consumers to “think of the $475,000 as parts, not labor.”
Hagop Kantarjian, MD, leukemia specialist and professor at the University of Texas MD Anderson Cancer Center, estimates tisagenlecleucel’s total cost could reach $1.5 million.
CAR T-cell therapy is expensive because of the unique way that it works. Doctors harvest patients’ immune cells, genetically alter them to rev up their ability to fight cancer, then reinfuse them into patients.
Taking the brakes off the immune system, Dr. Kantarjian said, can lead to life-threatening complications that require lengthy hospitalizations and expensive medications, which are prescribed in addition to conventional cancer therapy, rather than in place of it.
Keith D. Eaton, MD, a Seattle oncologist, said he ran up medical bills of $500,000 when he participated in a clinical trial of CAR T cells in 2013, even though all patients in the study received the medication for free. Dr. Eaton, who was diagnosed with acute lymphoblastic leukemia (ALL), spent nearly 2 months in the hospital.
Like Dr. Eaton, nearly half of patients who receive CAR T cells develop cytokine storm. Other serious side effects include strokelike symptoms and coma.
The cytokine storm felt like “the worst flu of your life,” said Dr. Eaton, now aged 51 years. His fever spiked so high that a hospital nurse assumed the thermometer was broken. Dr. Eaton replied, “It’s not broken. My temperature is too high to register on the thermometer.”
Although Dr. Eaton recovered, he wasn’t done with treatment. His doctors recommended a bone marrow transplant, another harrowing procedure, at a cost of hundreds of thousands of dollars.
Dr. Eaton said he feels fortunate to be healthy today, with tests showing no evidence of leukemia. His insurer paid for almost everything.
Kymriah’s sticker price is especially “outrageous” given its relatively low manufacturing costs, said Walid F. Gellad, MD, codirector of the Center for Pharmaceutical Policy and Prescribing at the University of Pittsburgh.
The gene therapy process used to create tisagenlecleucel costs about $15,000, according to a 2012 presentation by Carl H. June, MD, who pioneered CAR T-cell research at the University of Pennsylvania in Philadelphia. Dr. June could not be reached for comment.
To quell unrest about price, Novartis has offered patients and insurers a new twist on the money-back guarantee.
Novartis will charge for the drug only if patients go into remission within 1 month of treatment. In a key clinical trial, 83% of the children and young adults treated with tisagenlecleucel went into remission within 3 months. Novartis calls the plan “outcomes-based pricing.”
Novartis is “working through the specific details” of how the pricing plan will affect the Centers for Medicare & Medicaid Services, which pays for care for many cancer patients, company spokesperson Julie Masow said. “There are many hurdles” to this type of pricing plan but, Ms. Masow said, “Novartis is committed to making this happen.”
She also said that Kymriah’s manufacturing costs are much higher than $15,000, although she didn’t cite a specific dollar amount. She noted that Novartis has invested heavily in the technology, designing “an innovative manufacturing facility and process specifically for cellular therapies.”
As for Kymriah-related hospital and medication charges, “costs will vary from patient to patient and treatment center to treatment center, based on the level of care each patient requires,” Ms. Masow said. “Kymriah is a one-time treatment that has shown remarkable early, deep, and durable responses in these children who are very sick and often out of options.”
Some doctors said tisagenlecleucel, which could be used by about 600 patients a year, offers an incalculable benefit for desperately ill young people. The drug is approved for children and young adults with B-cell ALL who already have been treated with at least two other cancer therapies.
“A kid’s life is priceless,” said Michelle Hermiston, MD, director of pediatric immunotherapy at Benioff Children’s Hospital, at the University of California, San Francisco. “Any given kid has the potential to make financial impacts over a lifetime that far outweigh the cost of their cure. From this perspective, every child in my mind deserves the best curative therapy we can offer.”
Other cancer doctors say the Novartis plan is no bargain.
About 36% of patients who go into remission with tisagenlecleucel relapse within 1 year, said Vinay Prasad, MD, of Oregon Health & Science University, Portland. Many of these patients will need additional treatment, said Dr. Prasad, who wrote an editorial about tisagenlecleucel’s price Oct. 4 in Nature.
“If you’ve paid half a million dollars for drugs and half a million dollars for care, and a year later your cancer is back, is that a good deal?” asked Dr. Saltz, who cowrote a recent editorial on tisagenlecleucel’s price in JAMA.
Steve Miller, MD, chief medical officer for Express Scripts, said it would be more fair to judge Kymriah’s success after 6 months of treatment, rather than 1 month. Dr. Prasad goes even further. He said Novartis should issue refunds for any patient who relapses within 3 years.
A consumer-advocate group called Patients for Affordable Drugs also has said that tisagenlecleucel costs too much, given that the federal government spent more than $200 million over 2 decades to support the basic research into CAR T-cell therapy, long before Novartis bought the rights.
Rep. Lloyd Doggett (D-Texas) wrote a letter to the Medicare program’s director last month asking for details on how the Novartis payment deal will work.
“As Big Pharma continues to put price gouging before patient access, companies will point more and more proudly at their pricing agreements,” Rep. Doggett wrote. “But taxpayers deserve to know more about how these agreements will work – whether they will actually save the government money, defray these massive costs, and ensure that they can access lifesaving medications.”
KHN’s coverage related to aging & improving care of older adults is supported by The John A. Hartford Foundation. Kaiser Health News is a national health policy news service that is part of the nonpartisan Henry J. Kaiser Family Foundation.
Outrage over the high cost of cancer care has focused on skyrocketing drug prices, including the $475,000 price tag for the country’s first gene therapy, Novartis’ Kymriah (tisagenlecleucel), a leukemia treatment approved in August.
But the total costs of tisagenlecleucel and the 21 similar drugs in development – known as CAR T-cell therapies – will be far higher than many have imagined, reaching $1 million or more per patient, according to leading cancer experts. The next CAR T-cell drug could be approved as soon as November.
Although Kymriah’s price tag has “shattered oncology drug pricing norms,” said Leonard Saltz, MD, chief of gastrointestinal oncology at Memorial Sloan Kettering Cancer Center in New York, “the sticker price is just the starting point.”
These therapies lead to a cascade of costs, propelled by serious side effects that require sophisticated management, Dr. Saltz said. For this class of drugs, Dr, Saltz advised consumers to “think of the $475,000 as parts, not labor.”
Hagop Kantarjian, MD, leukemia specialist and professor at the University of Texas MD Anderson Cancer Center, estimates tisagenlecleucel’s total cost could reach $1.5 million.
CAR T-cell therapy is expensive because of the unique way that it works. Doctors harvest patients’ immune cells, genetically alter them to rev up their ability to fight cancer, then reinfuse them into patients.
Taking the brakes off the immune system, Dr. Kantarjian said, can lead to life-threatening complications that require lengthy hospitalizations and expensive medications, which are prescribed in addition to conventional cancer therapy, rather than in place of it.
Keith D. Eaton, MD, a Seattle oncologist, said he ran up medical bills of $500,000 when he participated in a clinical trial of CAR T cells in 2013, even though all patients in the study received the medication for free. Dr. Eaton, who was diagnosed with acute lymphoblastic leukemia (ALL), spent nearly 2 months in the hospital.
Like Dr. Eaton, nearly half of patients who receive CAR T cells develop cytokine storm. Other serious side effects include strokelike symptoms and coma.
The cytokine storm felt like “the worst flu of your life,” said Dr. Eaton, now aged 51 years. His fever spiked so high that a hospital nurse assumed the thermometer was broken. Dr. Eaton replied, “It’s not broken. My temperature is too high to register on the thermometer.”
Although Dr. Eaton recovered, he wasn’t done with treatment. His doctors recommended a bone marrow transplant, another harrowing procedure, at a cost of hundreds of thousands of dollars.
Dr. Eaton said he feels fortunate to be healthy today, with tests showing no evidence of leukemia. His insurer paid for almost everything.
Kymriah’s sticker price is especially “outrageous” given its relatively low manufacturing costs, said Walid F. Gellad, MD, codirector of the Center for Pharmaceutical Policy and Prescribing at the University of Pittsburgh.
The gene therapy process used to create tisagenlecleucel costs about $15,000, according to a 2012 presentation by Carl H. June, MD, who pioneered CAR T-cell research at the University of Pennsylvania in Philadelphia. Dr. June could not be reached for comment.
To quell unrest about price, Novartis has offered patients and insurers a new twist on the money-back guarantee.
Novartis will charge for the drug only if patients go into remission within 1 month of treatment. In a key clinical trial, 83% of the children and young adults treated with tisagenlecleucel went into remission within 3 months. Novartis calls the plan “outcomes-based pricing.”
Novartis is “working through the specific details” of how the pricing plan will affect the Centers for Medicare & Medicaid Services, which pays for care for many cancer patients, company spokesperson Julie Masow said. “There are many hurdles” to this type of pricing plan but, Ms. Masow said, “Novartis is committed to making this happen.”
She also said that Kymriah’s manufacturing costs are much higher than $15,000, although she didn’t cite a specific dollar amount. She noted that Novartis has invested heavily in the technology, designing “an innovative manufacturing facility and process specifically for cellular therapies.”
As for Kymriah-related hospital and medication charges, “costs will vary from patient to patient and treatment center to treatment center, based on the level of care each patient requires,” Ms. Masow said. “Kymriah is a one-time treatment that has shown remarkable early, deep, and durable responses in these children who are very sick and often out of options.”
Some doctors said tisagenlecleucel, which could be used by about 600 patients a year, offers an incalculable benefit for desperately ill young people. The drug is approved for children and young adults with B-cell ALL who already have been treated with at least two other cancer therapies.
“A kid’s life is priceless,” said Michelle Hermiston, MD, director of pediatric immunotherapy at Benioff Children’s Hospital, at the University of California, San Francisco. “Any given kid has the potential to make financial impacts over a lifetime that far outweigh the cost of their cure. From this perspective, every child in my mind deserves the best curative therapy we can offer.”
Other cancer doctors say the Novartis plan is no bargain.
About 36% of patients who go into remission with tisagenlecleucel relapse within 1 year, said Vinay Prasad, MD, of Oregon Health & Science University, Portland. Many of these patients will need additional treatment, said Dr. Prasad, who wrote an editorial about tisagenlecleucel’s price Oct. 4 in Nature.
“If you’ve paid half a million dollars for drugs and half a million dollars for care, and a year later your cancer is back, is that a good deal?” asked Dr. Saltz, who cowrote a recent editorial on tisagenlecleucel’s price in JAMA.
Steve Miller, MD, chief medical officer for Express Scripts, said it would be more fair to judge Kymriah’s success after 6 months of treatment, rather than 1 month. Dr. Prasad goes even further. He said Novartis should issue refunds for any patient who relapses within 3 years.
A consumer-advocate group called Patients for Affordable Drugs also has said that tisagenlecleucel costs too much, given that the federal government spent more than $200 million over 2 decades to support the basic research into CAR T-cell therapy, long before Novartis bought the rights.
Rep. Lloyd Doggett (D-Texas) wrote a letter to the Medicare program’s director last month asking for details on how the Novartis payment deal will work.
“As Big Pharma continues to put price gouging before patient access, companies will point more and more proudly at their pricing agreements,” Rep. Doggett wrote. “But taxpayers deserve to know more about how these agreements will work – whether they will actually save the government money, defray these massive costs, and ensure that they can access lifesaving medications.”
KHN’s coverage related to aging & improving care of older adults is supported by The John A. Hartford Foundation. Kaiser Health News is a national health policy news service that is part of the nonpartisan Henry J. Kaiser Family Foundation.