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Breakthrough drugs approved with less stringent criteria
Clinical trials supporting the approval of drugs with breakthrough therapy designation1 do not meet the same standards as trials for non-breakthrough drugs, according to researchers.
Between 2012 and 2017, the US Food and Drug Administration (FDA) approved 46 breakthrough therapeutics on the basis of 89 pivotal trials.
Researchers found these trials “commonly lacked randomization, double-blinding, and control groups, used surrogate markers as primary endpoints, and enrolled small numbers of patients.”
Joseph S. Ross, MD, of the Yale School of Medicine in New Haven, Connecticut, and his colleagues detailed these findings in a letter to JAMA.
“To be clear, I think the FDA, as directed by Congress, is doing everything it can to expedite the development and review of drugs that treat serious and life-threatening conditions,” Dr Ross said.
“Our research suggests that FDA approval of these breakthrough therapies is generally based on shorter and smaller clinical trials than those that support FDA approval of non-breakthrough therapy drugs.”
Analyzing the approvals
More than half of the 46 approvals analyzed were for cancer therapeutics (n=25; 54.3%), and an equal number were considered first-in-class.
All 46 products received priority review2, 30 (65.2%) received orphan designation3, 24 qualified for fast track4 review (52.2%), and 18 received accelerated approval5 (39.1%).
The median time from an investigational new drug activation to final FDA approval was 4.9 years. The median time from the submission of the new drug application to FDA approval was 6.9 months.
The median number of pivotal trials per indication was 1, and the median number of patients supporting an indication was 222.
Of all the approvals, 27 (58.7%) were made based on randomized trials, 21 (45.7%) were based on double-blind allocation, and 25 (54.3%) used an active or placebo comparator. Only 10 (21.7%) used a clinical primary endpoint.
The analysis also showed that trials supporting breakthrough drugs with accelerated approval were significantly less likely to be randomized, double-blinded, or have an active/placebo control group.
Of 18 trials that were used to grant drugs accelerated approval, 3 (16.7%) trials were randomized, 1 (5.6%) was double-blinded, and 3 (16.7%) had an active/placebo control group.
Of 28 trials supporting drugs without accelerated approval, 24 (85.7%) trials were randomized, 20 (71.4%) were double-blinded, and 22 (78.6%) had an active/placebo control group.
All 18 accelerated approvals had at least 1 safety analysis or efficacy-focused postmarketing requirement.
Dr Ross pointed out that when approvals are based on shorter and smaller clinical trials, there is greater uncertainty at the time of approval.
For example, will effects observed in a small, single trial be observed in a larger population or in another independent study? Will effects observed over a short period persist over time? Will new risks (or benefits) be observed over a longer period? And will the effect observed on the outcomes used in these shorter trials—usually surrogate endpoints believed to predict a clinical benefit—be confirmed by clinical outcomes?
“If we are going to be making this trade-off to allow novel drugs to come to market on the basis of evidence that is generally accompanied by greater uncertainty, we must be committed as a clinical and scientific community to ensuring that high-quality, rigorous postmarketing trials are conducted within a reasonable period of time,” Dr Ross said.
He noted that postmarketing trials will resolve some of the uncertainty and will ensure that drugs are associated with the benefit/safety profile that is expected based on the initial clinical studies.
“This will allow clinicians and patients to make fully informed decisions about whether to use these novel treatments,” he said.
1. The FDA’s breakthrough designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions. Breakthrough designation entitles sponsors to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as rolling submission and priority review. To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.
2. The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions. The FDA aims to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.
3. The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US. Orphan designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
4. The FDA’s fast track program is designed to expedite clinical development and submission of applications for drugs with the potential to treat serious or life-threatening conditions and address unmet medical needs. Fast track designation facilitates frequent interactions with the FDA review team, including meetings to discuss the drug’s development plan and written communications about issues such as trial design and use of biomarkers. Drugs that receive fast track designation may be eligible for accelerated approval and priority review if relevant criteria are met. Fast track drugs may also be eligible for rolling review, which allows a developer to submit individual sections of a drug’s application for review as they are ready, rather than waiting until all sections are complete.
5. The FDA’s accelerated approval program allows conditional approval of a drug that fills an unmet medical need for a serious condition. Accelerated approval is based on surrogate or intermediate endpoints that are reasonably likely to predict clinical benefit. Continued approval of drugs granted accelerated approval may be contingent upon verification of clinical benefit in confirmatory trials.
Clinical trials supporting the approval of drugs with breakthrough therapy designation1 do not meet the same standards as trials for non-breakthrough drugs, according to researchers.
Between 2012 and 2017, the US Food and Drug Administration (FDA) approved 46 breakthrough therapeutics on the basis of 89 pivotal trials.
Researchers found these trials “commonly lacked randomization, double-blinding, and control groups, used surrogate markers as primary endpoints, and enrolled small numbers of patients.”
Joseph S. Ross, MD, of the Yale School of Medicine in New Haven, Connecticut, and his colleagues detailed these findings in a letter to JAMA.
“To be clear, I think the FDA, as directed by Congress, is doing everything it can to expedite the development and review of drugs that treat serious and life-threatening conditions,” Dr Ross said.
“Our research suggests that FDA approval of these breakthrough therapies is generally based on shorter and smaller clinical trials than those that support FDA approval of non-breakthrough therapy drugs.”
Analyzing the approvals
More than half of the 46 approvals analyzed were for cancer therapeutics (n=25; 54.3%), and an equal number were considered first-in-class.
All 46 products received priority review2, 30 (65.2%) received orphan designation3, 24 qualified for fast track4 review (52.2%), and 18 received accelerated approval5 (39.1%).
The median time from an investigational new drug activation to final FDA approval was 4.9 years. The median time from the submission of the new drug application to FDA approval was 6.9 months.
The median number of pivotal trials per indication was 1, and the median number of patients supporting an indication was 222.
Of all the approvals, 27 (58.7%) were made based on randomized trials, 21 (45.7%) were based on double-blind allocation, and 25 (54.3%) used an active or placebo comparator. Only 10 (21.7%) used a clinical primary endpoint.
The analysis also showed that trials supporting breakthrough drugs with accelerated approval were significantly less likely to be randomized, double-blinded, or have an active/placebo control group.
Of 18 trials that were used to grant drugs accelerated approval, 3 (16.7%) trials were randomized, 1 (5.6%) was double-blinded, and 3 (16.7%) had an active/placebo control group.
Of 28 trials supporting drugs without accelerated approval, 24 (85.7%) trials were randomized, 20 (71.4%) were double-blinded, and 22 (78.6%) had an active/placebo control group.
All 18 accelerated approvals had at least 1 safety analysis or efficacy-focused postmarketing requirement.
Dr Ross pointed out that when approvals are based on shorter and smaller clinical trials, there is greater uncertainty at the time of approval.
For example, will effects observed in a small, single trial be observed in a larger population or in another independent study? Will effects observed over a short period persist over time? Will new risks (or benefits) be observed over a longer period? And will the effect observed on the outcomes used in these shorter trials—usually surrogate endpoints believed to predict a clinical benefit—be confirmed by clinical outcomes?
“If we are going to be making this trade-off to allow novel drugs to come to market on the basis of evidence that is generally accompanied by greater uncertainty, we must be committed as a clinical and scientific community to ensuring that high-quality, rigorous postmarketing trials are conducted within a reasonable period of time,” Dr Ross said.
He noted that postmarketing trials will resolve some of the uncertainty and will ensure that drugs are associated with the benefit/safety profile that is expected based on the initial clinical studies.
“This will allow clinicians and patients to make fully informed decisions about whether to use these novel treatments,” he said.
1. The FDA’s breakthrough designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions. Breakthrough designation entitles sponsors to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as rolling submission and priority review. To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.
2. The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions. The FDA aims to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.
3. The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US. Orphan designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
4. The FDA’s fast track program is designed to expedite clinical development and submission of applications for drugs with the potential to treat serious or life-threatening conditions and address unmet medical needs. Fast track designation facilitates frequent interactions with the FDA review team, including meetings to discuss the drug’s development plan and written communications about issues such as trial design and use of biomarkers. Drugs that receive fast track designation may be eligible for accelerated approval and priority review if relevant criteria are met. Fast track drugs may also be eligible for rolling review, which allows a developer to submit individual sections of a drug’s application for review as they are ready, rather than waiting until all sections are complete.
5. The FDA’s accelerated approval program allows conditional approval of a drug that fills an unmet medical need for a serious condition. Accelerated approval is based on surrogate or intermediate endpoints that are reasonably likely to predict clinical benefit. Continued approval of drugs granted accelerated approval may be contingent upon verification of clinical benefit in confirmatory trials.
Clinical trials supporting the approval of drugs with breakthrough therapy designation1 do not meet the same standards as trials for non-breakthrough drugs, according to researchers.
Between 2012 and 2017, the US Food and Drug Administration (FDA) approved 46 breakthrough therapeutics on the basis of 89 pivotal trials.
Researchers found these trials “commonly lacked randomization, double-blinding, and control groups, used surrogate markers as primary endpoints, and enrolled small numbers of patients.”
Joseph S. Ross, MD, of the Yale School of Medicine in New Haven, Connecticut, and his colleagues detailed these findings in a letter to JAMA.
“To be clear, I think the FDA, as directed by Congress, is doing everything it can to expedite the development and review of drugs that treat serious and life-threatening conditions,” Dr Ross said.
“Our research suggests that FDA approval of these breakthrough therapies is generally based on shorter and smaller clinical trials than those that support FDA approval of non-breakthrough therapy drugs.”
Analyzing the approvals
More than half of the 46 approvals analyzed were for cancer therapeutics (n=25; 54.3%), and an equal number were considered first-in-class.
All 46 products received priority review2, 30 (65.2%) received orphan designation3, 24 qualified for fast track4 review (52.2%), and 18 received accelerated approval5 (39.1%).
The median time from an investigational new drug activation to final FDA approval was 4.9 years. The median time from the submission of the new drug application to FDA approval was 6.9 months.
The median number of pivotal trials per indication was 1, and the median number of patients supporting an indication was 222.
Of all the approvals, 27 (58.7%) were made based on randomized trials, 21 (45.7%) were based on double-blind allocation, and 25 (54.3%) used an active or placebo comparator. Only 10 (21.7%) used a clinical primary endpoint.
The analysis also showed that trials supporting breakthrough drugs with accelerated approval were significantly less likely to be randomized, double-blinded, or have an active/placebo control group.
Of 18 trials that were used to grant drugs accelerated approval, 3 (16.7%) trials were randomized, 1 (5.6%) was double-blinded, and 3 (16.7%) had an active/placebo control group.
Of 28 trials supporting drugs without accelerated approval, 24 (85.7%) trials were randomized, 20 (71.4%) were double-blinded, and 22 (78.6%) had an active/placebo control group.
All 18 accelerated approvals had at least 1 safety analysis or efficacy-focused postmarketing requirement.
Dr Ross pointed out that when approvals are based on shorter and smaller clinical trials, there is greater uncertainty at the time of approval.
For example, will effects observed in a small, single trial be observed in a larger population or in another independent study? Will effects observed over a short period persist over time? Will new risks (or benefits) be observed over a longer period? And will the effect observed on the outcomes used in these shorter trials—usually surrogate endpoints believed to predict a clinical benefit—be confirmed by clinical outcomes?
“If we are going to be making this trade-off to allow novel drugs to come to market on the basis of evidence that is generally accompanied by greater uncertainty, we must be committed as a clinical and scientific community to ensuring that high-quality, rigorous postmarketing trials are conducted within a reasonable period of time,” Dr Ross said.
He noted that postmarketing trials will resolve some of the uncertainty and will ensure that drugs are associated with the benefit/safety profile that is expected based on the initial clinical studies.
“This will allow clinicians and patients to make fully informed decisions about whether to use these novel treatments,” he said.
1. The FDA’s breakthrough designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions. Breakthrough designation entitles sponsors to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as rolling submission and priority review. To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.
2. The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions. The FDA aims to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.
3. The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US. Orphan designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
4. The FDA’s fast track program is designed to expedite clinical development and submission of applications for drugs with the potential to treat serious or life-threatening conditions and address unmet medical needs. Fast track designation facilitates frequent interactions with the FDA review team, including meetings to discuss the drug’s development plan and written communications about issues such as trial design and use of biomarkers. Drugs that receive fast track designation may be eligible for accelerated approval and priority review if relevant criteria are met. Fast track drugs may also be eligible for rolling review, which allows a developer to submit individual sections of a drug’s application for review as they are ready, rather than waiting until all sections are complete.
5. The FDA’s accelerated approval program allows conditional approval of a drug that fills an unmet medical need for a serious condition. Accelerated approval is based on surrogate or intermediate endpoints that are reasonably likely to predict clinical benefit. Continued approval of drugs granted accelerated approval may be contingent upon verification of clinical benefit in confirmatory trials.
Health Canada expands approval of obinutuzumab
Health Canada has expanded the approved use of obinutuzumab (Gazyva®).
The anti-CD20 monoclonal antibody is now approved for use in combination with chemotherapy to treat patients with previously untreated follicular lymphoma (FL) that is advanced (stage II bulky, stage III, or stage IV).
In patients who respond to this treatment, obinutuzumab monotherapy can be given as maintenance.
Health Canada previously approved obinutuzumab for the following indications:
- In combination with chlorambucil to treat patients with previously untreated chronic lymphocytic leukemia
- First in combination with bendamustine, then as monotherapy, in FL patients who relapsed after or are refractory to a rituximab-containing regimen.
Phase 3 results
Health Canada’s latest approval of obinutuzumab is based on results from the phase 3 GALLIUM study, which were published in NEJM in October 2017. The following are updated data from the product monograph.
GALLIUM included 1385 patients with previously untreated non-Hodgkin lymphoma, and 1202 of these patients had previously untreated, advanced FL.
Half of the FL patients (n=601) were randomized to receive obinutuzumab plus chemotherapy (followed by obinutuzumab maintenance for up to 2 years), and half were randomized to rituximab plus chemotherapy (followed by rituximab maintenance for up to 2 years).
The different chemotherapies used were CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), CVP (cyclophosphamide, vincristine, and prednisone), and bendamustine.
At a median observation time of 41.1 months, the overall response rate was 91% in the obinutuzumab arm and 88% in the rituximab arm. The complete response rates were 28% and 27%, respectively.
The median progression-free survival was not reached in either arm. The hazard ratio, for obinutuzumab compared to rituximab, was 0.72 (95% CI, 0.56-0.93, P=0.0118).
The estimated 3-year progression-free survival was 78.9% in the rituximab arm and 83.4% in the obinutuzumab arm.
Safety was evaluated based on all 1385 patients in the study, 86% of whom had FL and 14% of whom had marginal zone lymphoma.
Serious adverse events (AEs) occurred in 50% of patients in the obinutuzumab arm and 43% in the rituximab arm. Fatal AEs occurred in 5% and 4%, respectively. Infections and second malignancies were the leading causes of these deaths.
During the monotherapy period, the most common AEs (≥ 5%) in patients treated with obinutuzumab were cough (21%), neutropenia (19%), upper respiratory tract infection (15%), viral upper respiratory tract infection (15%), diarrhea (13%), arthralgia (10%), fatigue (9%), sinusitis (9%), infusion reactions (8%), pneumonia (8%), herpes zoster (8%), lower respiratory tract infection (7%), pyrexia (7%), back pain (6%), headache (6%), urinary tract infection (6%), nausea (6%), bronchitis (5%), and vomiting (5%).
Grade 3-4 AEs (≥1%) in patients treated with obinutuzumab included neutropenia (17%), pneumonia (3%), and febrile neutropenia (2%). There were 2 deaths due to pneumonia in the obinutuzumab arm.
Health Canada has expanded the approved use of obinutuzumab (Gazyva®).
The anti-CD20 monoclonal antibody is now approved for use in combination with chemotherapy to treat patients with previously untreated follicular lymphoma (FL) that is advanced (stage II bulky, stage III, or stage IV).
In patients who respond to this treatment, obinutuzumab monotherapy can be given as maintenance.
Health Canada previously approved obinutuzumab for the following indications:
- In combination with chlorambucil to treat patients with previously untreated chronic lymphocytic leukemia
- First in combination with bendamustine, then as monotherapy, in FL patients who relapsed after or are refractory to a rituximab-containing regimen.
Phase 3 results
Health Canada’s latest approval of obinutuzumab is based on results from the phase 3 GALLIUM study, which were published in NEJM in October 2017. The following are updated data from the product monograph.
GALLIUM included 1385 patients with previously untreated non-Hodgkin lymphoma, and 1202 of these patients had previously untreated, advanced FL.
Half of the FL patients (n=601) were randomized to receive obinutuzumab plus chemotherapy (followed by obinutuzumab maintenance for up to 2 years), and half were randomized to rituximab plus chemotherapy (followed by rituximab maintenance for up to 2 years).
The different chemotherapies used were CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), CVP (cyclophosphamide, vincristine, and prednisone), and bendamustine.
At a median observation time of 41.1 months, the overall response rate was 91% in the obinutuzumab arm and 88% in the rituximab arm. The complete response rates were 28% and 27%, respectively.
The median progression-free survival was not reached in either arm. The hazard ratio, for obinutuzumab compared to rituximab, was 0.72 (95% CI, 0.56-0.93, P=0.0118).
The estimated 3-year progression-free survival was 78.9% in the rituximab arm and 83.4% in the obinutuzumab arm.
Safety was evaluated based on all 1385 patients in the study, 86% of whom had FL and 14% of whom had marginal zone lymphoma.
Serious adverse events (AEs) occurred in 50% of patients in the obinutuzumab arm and 43% in the rituximab arm. Fatal AEs occurred in 5% and 4%, respectively. Infections and second malignancies were the leading causes of these deaths.
During the monotherapy period, the most common AEs (≥ 5%) in patients treated with obinutuzumab were cough (21%), neutropenia (19%), upper respiratory tract infection (15%), viral upper respiratory tract infection (15%), diarrhea (13%), arthralgia (10%), fatigue (9%), sinusitis (9%), infusion reactions (8%), pneumonia (8%), herpes zoster (8%), lower respiratory tract infection (7%), pyrexia (7%), back pain (6%), headache (6%), urinary tract infection (6%), nausea (6%), bronchitis (5%), and vomiting (5%).
Grade 3-4 AEs (≥1%) in patients treated with obinutuzumab included neutropenia (17%), pneumonia (3%), and febrile neutropenia (2%). There were 2 deaths due to pneumonia in the obinutuzumab arm.
Health Canada has expanded the approved use of obinutuzumab (Gazyva®).
The anti-CD20 monoclonal antibody is now approved for use in combination with chemotherapy to treat patients with previously untreated follicular lymphoma (FL) that is advanced (stage II bulky, stage III, or stage IV).
In patients who respond to this treatment, obinutuzumab monotherapy can be given as maintenance.
Health Canada previously approved obinutuzumab for the following indications:
- In combination with chlorambucil to treat patients with previously untreated chronic lymphocytic leukemia
- First in combination with bendamustine, then as monotherapy, in FL patients who relapsed after or are refractory to a rituximab-containing regimen.
Phase 3 results
Health Canada’s latest approval of obinutuzumab is based on results from the phase 3 GALLIUM study, which were published in NEJM in October 2017. The following are updated data from the product monograph.
GALLIUM included 1385 patients with previously untreated non-Hodgkin lymphoma, and 1202 of these patients had previously untreated, advanced FL.
Half of the FL patients (n=601) were randomized to receive obinutuzumab plus chemotherapy (followed by obinutuzumab maintenance for up to 2 years), and half were randomized to rituximab plus chemotherapy (followed by rituximab maintenance for up to 2 years).
The different chemotherapies used were CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), CVP (cyclophosphamide, vincristine, and prednisone), and bendamustine.
At a median observation time of 41.1 months, the overall response rate was 91% in the obinutuzumab arm and 88% in the rituximab arm. The complete response rates were 28% and 27%, respectively.
The median progression-free survival was not reached in either arm. The hazard ratio, for obinutuzumab compared to rituximab, was 0.72 (95% CI, 0.56-0.93, P=0.0118).
The estimated 3-year progression-free survival was 78.9% in the rituximab arm and 83.4% in the obinutuzumab arm.
Safety was evaluated based on all 1385 patients in the study, 86% of whom had FL and 14% of whom had marginal zone lymphoma.
Serious adverse events (AEs) occurred in 50% of patients in the obinutuzumab arm and 43% in the rituximab arm. Fatal AEs occurred in 5% and 4%, respectively. Infections and second malignancies were the leading causes of these deaths.
During the monotherapy period, the most common AEs (≥ 5%) in patients treated with obinutuzumab were cough (21%), neutropenia (19%), upper respiratory tract infection (15%), viral upper respiratory tract infection (15%), diarrhea (13%), arthralgia (10%), fatigue (9%), sinusitis (9%), infusion reactions (8%), pneumonia (8%), herpes zoster (8%), lower respiratory tract infection (7%), pyrexia (7%), back pain (6%), headache (6%), urinary tract infection (6%), nausea (6%), bronchitis (5%), and vomiting (5%).
Grade 3-4 AEs (≥1%) in patients treated with obinutuzumab included neutropenia (17%), pneumonia (3%), and febrile neutropenia (2%). There were 2 deaths due to pneumonia in the obinutuzumab arm.
Conflicts of interest among FDA advisers
An investigative report has unearthed potential conflicts of interest among physicians who serve on advisory panels for the US Food and Drug Administration (FDA).
The investigation revealed that some FDA advisers are receiving significant post-hoc payments from the makers of drugs they reviewed.
The investigation also uncovered relationships between advisers and drug companies that predate drug reviews.
Journalist Charles Piller and his colleagues conducted this investigation and detailed the results in Science.
The report includes data—from the federal Open Payments website—on 107 physicians who voted on FDA advisory committees between 2013 and 2016.
Forty of these advisers received more than $10,000 in post-hoc earnings or research support from the makers of drugs they reviewed or from competing drug companies.
Twenty-six advisers received more than $100,000, and 7 advisers received more than $1 million.
The 17 top earners received more than $300,000 each. For these advisers, 94% of their earnings came from the makers of drugs they previously reviewed or from those companies’ competitors.
The data also show that some advisers received funds from drug companies concurrent with or in the year before their advisory service.
Of the 17 top-earning advisers, 11 received financial support from competing companies on one or more of the drugs they reviewed. Five advisers also received support from the makers of one or more of the drugs reviewed.
The FDA did not disclose this information to the public or issue waivers for these potential conflicts. The FDA can issue a waiver to allow the participation of an adviser with an active conflict or one that ended in the year before a vote, as long as the adviser in question can provide expertise that cannot be provided by someone else.
It is possible that the FDA dismissed the aforementioned financial ties that predated drug reviews, deciding these relationships were not conflicts and did not require a waiver. However, it is also possible that the FDA did not know about these potential conflicts.
Piller and his colleagues were unable to determine what the FDA knew, as the agency refused to release disclosure documents, discuss individual advisers, or explain what steps, if any, the FDA takes to validate advisers’ disclosures.
An investigative report has unearthed potential conflicts of interest among physicians who serve on advisory panels for the US Food and Drug Administration (FDA).
The investigation revealed that some FDA advisers are receiving significant post-hoc payments from the makers of drugs they reviewed.
The investigation also uncovered relationships between advisers and drug companies that predate drug reviews.
Journalist Charles Piller and his colleagues conducted this investigation and detailed the results in Science.
The report includes data—from the federal Open Payments website—on 107 physicians who voted on FDA advisory committees between 2013 and 2016.
Forty of these advisers received more than $10,000 in post-hoc earnings or research support from the makers of drugs they reviewed or from competing drug companies.
Twenty-six advisers received more than $100,000, and 7 advisers received more than $1 million.
The 17 top earners received more than $300,000 each. For these advisers, 94% of their earnings came from the makers of drugs they previously reviewed or from those companies’ competitors.
The data also show that some advisers received funds from drug companies concurrent with or in the year before their advisory service.
Of the 17 top-earning advisers, 11 received financial support from competing companies on one or more of the drugs they reviewed. Five advisers also received support from the makers of one or more of the drugs reviewed.
The FDA did not disclose this information to the public or issue waivers for these potential conflicts. The FDA can issue a waiver to allow the participation of an adviser with an active conflict or one that ended in the year before a vote, as long as the adviser in question can provide expertise that cannot be provided by someone else.
It is possible that the FDA dismissed the aforementioned financial ties that predated drug reviews, deciding these relationships were not conflicts and did not require a waiver. However, it is also possible that the FDA did not know about these potential conflicts.
Piller and his colleagues were unable to determine what the FDA knew, as the agency refused to release disclosure documents, discuss individual advisers, or explain what steps, if any, the FDA takes to validate advisers’ disclosures.
An investigative report has unearthed potential conflicts of interest among physicians who serve on advisory panels for the US Food and Drug Administration (FDA).
The investigation revealed that some FDA advisers are receiving significant post-hoc payments from the makers of drugs they reviewed.
The investigation also uncovered relationships between advisers and drug companies that predate drug reviews.
Journalist Charles Piller and his colleagues conducted this investigation and detailed the results in Science.
The report includes data—from the federal Open Payments website—on 107 physicians who voted on FDA advisory committees between 2013 and 2016.
Forty of these advisers received more than $10,000 in post-hoc earnings or research support from the makers of drugs they reviewed or from competing drug companies.
Twenty-six advisers received more than $100,000, and 7 advisers received more than $1 million.
The 17 top earners received more than $300,000 each. For these advisers, 94% of their earnings came from the makers of drugs they previously reviewed or from those companies’ competitors.
The data also show that some advisers received funds from drug companies concurrent with or in the year before their advisory service.
Of the 17 top-earning advisers, 11 received financial support from competing companies on one or more of the drugs they reviewed. Five advisers also received support from the makers of one or more of the drugs reviewed.
The FDA did not disclose this information to the public or issue waivers for these potential conflicts. The FDA can issue a waiver to allow the participation of an adviser with an active conflict or one that ended in the year before a vote, as long as the adviser in question can provide expertise that cannot be provided by someone else.
It is possible that the FDA dismissed the aforementioned financial ties that predated drug reviews, deciding these relationships were not conflicts and did not require a waiver. However, it is also possible that the FDA did not know about these potential conflicts.
Piller and his colleagues were unable to determine what the FDA knew, as the agency refused to release disclosure documents, discuss individual advisers, or explain what steps, if any, the FDA takes to validate advisers’ disclosures.
EC approves new use, formulation of dasatinib
The European Commission (EC) has expanded the marketing authorization for dasatinib (Sprycel).
The drug is now approved to treat patients ages 1 to 18 with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase (CP).
The EC has also approved a new formulation of dasatinib—a powder for oral suspension (PFOS) intended for patients who cannot swallow tablets whole or who weigh 10 kg or less.
Dasatinib is also EC-approved to treat adults with:
- Newly diagnosed Ph+ CML-CP
- Chronic, accelerated, or blast phase CML with resistance or intolerance to prior therapy, including imatinib
- Ph+ acute lymphoblastic leukemia and lymphoid blast CML with resistance or intolerance to prior therapy.
The EC’s latest approval of dasatinib is supported by results from a phase 2 trial (NCT00777036), which were published in the Journal of Clinical Oncology in March.
The trial included 29 patients with imatinib-resistant/intolerant CML-CP and 84 patients with newly diagnosed CML-CP.
The previously treated patients received dasatinib tablets. Newly diagnosed patients were treated with dasatinib tablets (n=51) or PFOS (n=33).
Patients who started on PFOS could switch to tablets after receiving PFOS for at least 1 year. Sixty-seven percent of patients on PFOS switched to tablets due to patient preference.
The average daily dose of dasatinib was 58.18 mg/m2 in the previously treated patients and 59.84 mg/m2 in the newly diagnosed patients (for both tablets and PFOS). The median duration of treatment was 49.91 months (range, 1.9 to 90.2) and 42.30 months (range, 0.1 to 75.2), respectively.
Rates of confirmed complete hematologic response (CHR) at any time were 93% in the previously treated patients and 96% in the newly diagnosed patients.
At 12 months, previously treated patients had a major molecular response (MMR) rate of 41% and a complete molecular response (CMR) rate of 7%. In newly diagnosed patients, MMR was 52%, and CMR was 8%.
At 24 months, previously treated patients had an MMR rate of 55% and a CMR rate of 17%. In the newly diagnosed patients, MMR was 70%, and CMR was 21%.
The rate of major cytogenetic response (MCyR) at any time was 89.7% in all previously treated patients and 90% when the researchers excluded patients with MCyR or unknown cytogenetic status at baseline.
The rate of complete cytogenetic response (CCyR) at any time was 94% in all newly diagnosed patients and 93.9% when the researchers excluded patients with CCyR or unknown cytogenetic status at baseline.
The median progression-free survival and overall survival had not been reached at last follow-up.
The estimated 48-month progression-free survival was 78% in the previously treated patients and 93% in the newly diagnosed patients. The estimated 48-month overall survival was 96% and 100%, respectively.
Dasatinib-related adverse events (AEs) occurring in at least 10% of the previously treated patients included nausea/vomiting (31%), myalgia/arthralgia (17%), fatigue (14%), rash (14%), diarrhea (14%), hemorrhage (10%), bone growth and development events (10%), and shortness of breath (10%).
Dasatinib-related AEs occurring in at least 10% of the newly diagnosed patients included nausea/vomiting (20%), myalgia/arthralgia (10%), fatigue (11%), rash (19%), diarrhea (18%), and hemorrhage (10%).
The European Commission (EC) has expanded the marketing authorization for dasatinib (Sprycel).
The drug is now approved to treat patients ages 1 to 18 with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase (CP).
The EC has also approved a new formulation of dasatinib—a powder for oral suspension (PFOS) intended for patients who cannot swallow tablets whole or who weigh 10 kg or less.
Dasatinib is also EC-approved to treat adults with:
- Newly diagnosed Ph+ CML-CP
- Chronic, accelerated, or blast phase CML with resistance or intolerance to prior therapy, including imatinib
- Ph+ acute lymphoblastic leukemia and lymphoid blast CML with resistance or intolerance to prior therapy.
The EC’s latest approval of dasatinib is supported by results from a phase 2 trial (NCT00777036), which were published in the Journal of Clinical Oncology in March.
The trial included 29 patients with imatinib-resistant/intolerant CML-CP and 84 patients with newly diagnosed CML-CP.
The previously treated patients received dasatinib tablets. Newly diagnosed patients were treated with dasatinib tablets (n=51) or PFOS (n=33).
Patients who started on PFOS could switch to tablets after receiving PFOS for at least 1 year. Sixty-seven percent of patients on PFOS switched to tablets due to patient preference.
The average daily dose of dasatinib was 58.18 mg/m2 in the previously treated patients and 59.84 mg/m2 in the newly diagnosed patients (for both tablets and PFOS). The median duration of treatment was 49.91 months (range, 1.9 to 90.2) and 42.30 months (range, 0.1 to 75.2), respectively.
Rates of confirmed complete hematologic response (CHR) at any time were 93% in the previously treated patients and 96% in the newly diagnosed patients.
At 12 months, previously treated patients had a major molecular response (MMR) rate of 41% and a complete molecular response (CMR) rate of 7%. In newly diagnosed patients, MMR was 52%, and CMR was 8%.
At 24 months, previously treated patients had an MMR rate of 55% and a CMR rate of 17%. In the newly diagnosed patients, MMR was 70%, and CMR was 21%.
The rate of major cytogenetic response (MCyR) at any time was 89.7% in all previously treated patients and 90% when the researchers excluded patients with MCyR or unknown cytogenetic status at baseline.
The rate of complete cytogenetic response (CCyR) at any time was 94% in all newly diagnosed patients and 93.9% when the researchers excluded patients with CCyR or unknown cytogenetic status at baseline.
The median progression-free survival and overall survival had not been reached at last follow-up.
The estimated 48-month progression-free survival was 78% in the previously treated patients and 93% in the newly diagnosed patients. The estimated 48-month overall survival was 96% and 100%, respectively.
Dasatinib-related adverse events (AEs) occurring in at least 10% of the previously treated patients included nausea/vomiting (31%), myalgia/arthralgia (17%), fatigue (14%), rash (14%), diarrhea (14%), hemorrhage (10%), bone growth and development events (10%), and shortness of breath (10%).
Dasatinib-related AEs occurring in at least 10% of the newly diagnosed patients included nausea/vomiting (20%), myalgia/arthralgia (10%), fatigue (11%), rash (19%), diarrhea (18%), and hemorrhage (10%).
The European Commission (EC) has expanded the marketing authorization for dasatinib (Sprycel).
The drug is now approved to treat patients ages 1 to 18 with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase (CP).
The EC has also approved a new formulation of dasatinib—a powder for oral suspension (PFOS) intended for patients who cannot swallow tablets whole or who weigh 10 kg or less.
Dasatinib is also EC-approved to treat adults with:
- Newly diagnosed Ph+ CML-CP
- Chronic, accelerated, or blast phase CML with resistance or intolerance to prior therapy, including imatinib
- Ph+ acute lymphoblastic leukemia and lymphoid blast CML with resistance or intolerance to prior therapy.
The EC’s latest approval of dasatinib is supported by results from a phase 2 trial (NCT00777036), which were published in the Journal of Clinical Oncology in March.
The trial included 29 patients with imatinib-resistant/intolerant CML-CP and 84 patients with newly diagnosed CML-CP.
The previously treated patients received dasatinib tablets. Newly diagnosed patients were treated with dasatinib tablets (n=51) or PFOS (n=33).
Patients who started on PFOS could switch to tablets after receiving PFOS for at least 1 year. Sixty-seven percent of patients on PFOS switched to tablets due to patient preference.
The average daily dose of dasatinib was 58.18 mg/m2 in the previously treated patients and 59.84 mg/m2 in the newly diagnosed patients (for both tablets and PFOS). The median duration of treatment was 49.91 months (range, 1.9 to 90.2) and 42.30 months (range, 0.1 to 75.2), respectively.
Rates of confirmed complete hematologic response (CHR) at any time were 93% in the previously treated patients and 96% in the newly diagnosed patients.
At 12 months, previously treated patients had a major molecular response (MMR) rate of 41% and a complete molecular response (CMR) rate of 7%. In newly diagnosed patients, MMR was 52%, and CMR was 8%.
At 24 months, previously treated patients had an MMR rate of 55% and a CMR rate of 17%. In the newly diagnosed patients, MMR was 70%, and CMR was 21%.
The rate of major cytogenetic response (MCyR) at any time was 89.7% in all previously treated patients and 90% when the researchers excluded patients with MCyR or unknown cytogenetic status at baseline.
The rate of complete cytogenetic response (CCyR) at any time was 94% in all newly diagnosed patients and 93.9% when the researchers excluded patients with CCyR or unknown cytogenetic status at baseline.
The median progression-free survival and overall survival had not been reached at last follow-up.
The estimated 48-month progression-free survival was 78% in the previously treated patients and 93% in the newly diagnosed patients. The estimated 48-month overall survival was 96% and 100%, respectively.
Dasatinib-related adverse events (AEs) occurring in at least 10% of the previously treated patients included nausea/vomiting (31%), myalgia/arthralgia (17%), fatigue (14%), rash (14%), diarrhea (14%), hemorrhage (10%), bone growth and development events (10%), and shortness of breath (10%).
Dasatinib-related AEs occurring in at least 10% of the newly diagnosed patients included nausea/vomiting (20%), myalgia/arthralgia (10%), fatigue (11%), rash (19%), diarrhea (18%), and hemorrhage (10%).
CHMP recommends CAR T for ALL, DLBCL
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended the approval of tisagenlecleucel (Kymriah®, formerly CTL019) for 2 indications.
According to the CHMP, the chimeric antigen receptor (CAR) T-cell therapy should be approved to treat adults with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) who have received 2 or more lines of systemic therapy and patients up to 25 years of age who have B-cell acute lymphoblastic leukemia (ALL) that is refractory, in relapse post-transplant, or in second or later relapse.
The CHMP’s recommendation will be reviewed by the European Commission, which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.
The European Commission usually makes a decision within 67 days of the CHMP’s recommendation.
The CHMP’s recommendation is based on results from a pair of phase 2 trials—ELIANA and JULIET.
JULIET trial
Updated results from JULIET were presented at the recent 23rd Annual Congress of the European Hematology Association (EHA) as abstract S799.
The trial enrolled 165 adults with relapsed/refractory DLBCL, and 111 of them received a single infusion of tisagenlecleucel. Most of the patients who discontinued before dosing did so due to disease progression or clinical deterioration. The patients’ median age at baseline was 56 (range, 22-76).
Ninety-two percent of patients received bridging therapy, and 93% received lymphodepleting chemotherapy prior to tisagenlecleucel.
The median time from infusion to data cutoff was 13.9 months.
The overall response rate was 52%, and the complete response (CR) rate was 40%. Of the patients in CR at month 3, 83% remained in CR at month 12. The median duration of response was not reached.
At the time of data cutoff, none of the responders had proceeded to stem cell transplant.
For all infused patients (n=111), the 12-month overall survival (OS) rate was 49%, and the median OS was 11.7 months. The median OS was not reached for patients in CR.
Within 8 weeks of tisagenlecleucel infusion, 22% of patients had developed grade 3/4 cytokine release syndrome (CRS). Fifteen percent of patients received tocilizumab for CRS, including 3% of patients with grade 2 CRS and 50% of patients with grade 3 CRS.
Other adverse events (AEs) of interest included grade 3/4 neurologic events (12%), grade 3/4 cytopenias lasting more than 28 days (32%), grade 3/4 infections (20%), and grade 3/4 febrile neutropenia (15%).
ELIANA trial
Updated results from ELIANA were published in NEJM in February.
The trial included 75 children and young adults with relapsed/refractory ALL. The patients’ median age was 11 (range, 3 to 23).
All 75 patients received a single infusion of tisagenlecleucel, and 72 received lymphodepleting chemotherapy.
The median duration of follow-up was 13.1 months. The study’s primary endpoint was overall remission rate, which was defined as the rate of a best overall response of either CR or CR with incomplete hematologic recovery (CRi) within 3 months.
The overall remission rate was 81% (61/75), with 60% of patients (n=45) achieving a CR and 21% (n=16) achieving a CRi.
All patients whose best response was CR/CRi were negative for minimal residual disease. The median duration of response was not met.
Eight patients proceeded to transplant while in remission. At last follow-up, 4 were still in remission, and 4 had unknown disease status.
At 6 months, the event-free survival rate was 73%, and the OS rate was 90%. At 12 months, the rates were 50% and 76%, respectively.
All patients experienced at least 1 AE, and 95% had AEs thought to be related to tisagenlecleucel. The rate of grade 3/4 AEs was 88%, and the rate of related grade 3/4 AEs was 73%.
AEs of special interest included CRS (77%), neurologic events (40%), infections (43%), febrile neutropenia (35%), cytopenias not resolved by day 28 (37%), and tumor lysis syndrome (4%).
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended the approval of tisagenlecleucel (Kymriah®, formerly CTL019) for 2 indications.
According to the CHMP, the chimeric antigen receptor (CAR) T-cell therapy should be approved to treat adults with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) who have received 2 or more lines of systemic therapy and patients up to 25 years of age who have B-cell acute lymphoblastic leukemia (ALL) that is refractory, in relapse post-transplant, or in second or later relapse.
The CHMP’s recommendation will be reviewed by the European Commission, which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.
The European Commission usually makes a decision within 67 days of the CHMP’s recommendation.
The CHMP’s recommendation is based on results from a pair of phase 2 trials—ELIANA and JULIET.
JULIET trial
Updated results from JULIET were presented at the recent 23rd Annual Congress of the European Hematology Association (EHA) as abstract S799.
The trial enrolled 165 adults with relapsed/refractory DLBCL, and 111 of them received a single infusion of tisagenlecleucel. Most of the patients who discontinued before dosing did so due to disease progression or clinical deterioration. The patients’ median age at baseline was 56 (range, 22-76).
Ninety-two percent of patients received bridging therapy, and 93% received lymphodepleting chemotherapy prior to tisagenlecleucel.
The median time from infusion to data cutoff was 13.9 months.
The overall response rate was 52%, and the complete response (CR) rate was 40%. Of the patients in CR at month 3, 83% remained in CR at month 12. The median duration of response was not reached.
At the time of data cutoff, none of the responders had proceeded to stem cell transplant.
For all infused patients (n=111), the 12-month overall survival (OS) rate was 49%, and the median OS was 11.7 months. The median OS was not reached for patients in CR.
Within 8 weeks of tisagenlecleucel infusion, 22% of patients had developed grade 3/4 cytokine release syndrome (CRS). Fifteen percent of patients received tocilizumab for CRS, including 3% of patients with grade 2 CRS and 50% of patients with grade 3 CRS.
Other adverse events (AEs) of interest included grade 3/4 neurologic events (12%), grade 3/4 cytopenias lasting more than 28 days (32%), grade 3/4 infections (20%), and grade 3/4 febrile neutropenia (15%).
ELIANA trial
Updated results from ELIANA were published in NEJM in February.
The trial included 75 children and young adults with relapsed/refractory ALL. The patients’ median age was 11 (range, 3 to 23).
All 75 patients received a single infusion of tisagenlecleucel, and 72 received lymphodepleting chemotherapy.
The median duration of follow-up was 13.1 months. The study’s primary endpoint was overall remission rate, which was defined as the rate of a best overall response of either CR or CR with incomplete hematologic recovery (CRi) within 3 months.
The overall remission rate was 81% (61/75), with 60% of patients (n=45) achieving a CR and 21% (n=16) achieving a CRi.
All patients whose best response was CR/CRi were negative for minimal residual disease. The median duration of response was not met.
Eight patients proceeded to transplant while in remission. At last follow-up, 4 were still in remission, and 4 had unknown disease status.
At 6 months, the event-free survival rate was 73%, and the OS rate was 90%. At 12 months, the rates were 50% and 76%, respectively.
All patients experienced at least 1 AE, and 95% had AEs thought to be related to tisagenlecleucel. The rate of grade 3/4 AEs was 88%, and the rate of related grade 3/4 AEs was 73%.
AEs of special interest included CRS (77%), neurologic events (40%), infections (43%), febrile neutropenia (35%), cytopenias not resolved by day 28 (37%), and tumor lysis syndrome (4%).
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended the approval of tisagenlecleucel (Kymriah®, formerly CTL019) for 2 indications.
According to the CHMP, the chimeric antigen receptor (CAR) T-cell therapy should be approved to treat adults with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) who have received 2 or more lines of systemic therapy and patients up to 25 years of age who have B-cell acute lymphoblastic leukemia (ALL) that is refractory, in relapse post-transplant, or in second or later relapse.
The CHMP’s recommendation will be reviewed by the European Commission, which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.
The European Commission usually makes a decision within 67 days of the CHMP’s recommendation.
The CHMP’s recommendation is based on results from a pair of phase 2 trials—ELIANA and JULIET.
JULIET trial
Updated results from JULIET were presented at the recent 23rd Annual Congress of the European Hematology Association (EHA) as abstract S799.
The trial enrolled 165 adults with relapsed/refractory DLBCL, and 111 of them received a single infusion of tisagenlecleucel. Most of the patients who discontinued before dosing did so due to disease progression or clinical deterioration. The patients’ median age at baseline was 56 (range, 22-76).
Ninety-two percent of patients received bridging therapy, and 93% received lymphodepleting chemotherapy prior to tisagenlecleucel.
The median time from infusion to data cutoff was 13.9 months.
The overall response rate was 52%, and the complete response (CR) rate was 40%. Of the patients in CR at month 3, 83% remained in CR at month 12. The median duration of response was not reached.
At the time of data cutoff, none of the responders had proceeded to stem cell transplant.
For all infused patients (n=111), the 12-month overall survival (OS) rate was 49%, and the median OS was 11.7 months. The median OS was not reached for patients in CR.
Within 8 weeks of tisagenlecleucel infusion, 22% of patients had developed grade 3/4 cytokine release syndrome (CRS). Fifteen percent of patients received tocilizumab for CRS, including 3% of patients with grade 2 CRS and 50% of patients with grade 3 CRS.
Other adverse events (AEs) of interest included grade 3/4 neurologic events (12%), grade 3/4 cytopenias lasting more than 28 days (32%), grade 3/4 infections (20%), and grade 3/4 febrile neutropenia (15%).
ELIANA trial
Updated results from ELIANA were published in NEJM in February.
The trial included 75 children and young adults with relapsed/refractory ALL. The patients’ median age was 11 (range, 3 to 23).
All 75 patients received a single infusion of tisagenlecleucel, and 72 received lymphodepleting chemotherapy.
The median duration of follow-up was 13.1 months. The study’s primary endpoint was overall remission rate, which was defined as the rate of a best overall response of either CR or CR with incomplete hematologic recovery (CRi) within 3 months.
The overall remission rate was 81% (61/75), with 60% of patients (n=45) achieving a CR and 21% (n=16) achieving a CRi.
All patients whose best response was CR/CRi were negative for minimal residual disease. The median duration of response was not met.
Eight patients proceeded to transplant while in remission. At last follow-up, 4 were still in remission, and 4 had unknown disease status.
At 6 months, the event-free survival rate was 73%, and the OS rate was 90%. At 12 months, the rates were 50% and 76%, respectively.
All patients experienced at least 1 AE, and 95% had AEs thought to be related to tisagenlecleucel. The rate of grade 3/4 AEs was 88%, and the rate of related grade 3/4 AEs was 73%.
AEs of special interest included CRS (77%), neurologic events (40%), infections (43%), febrile neutropenia (35%), cytopenias not resolved by day 28 (37%), and tumor lysis syndrome (4%).
CHMP recommends CAR T for DLBCL, PMBCL
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval for the chimeric antigen receptor (CAR) T-cell therapy axicabtagene ciloleucel (Yescarta®, formerly KTE-C19).
The recommendation pertains to axicabtagene ciloleucel as a treatment for adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) or primary mediastinal large B-cell lymphoma (PMBCL) who have received 2 or more lines of systemic therapy.
The CHMP’s recommendation will be reviewed by the European Commission, which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.
The European Commission usually makes a decision within 67 days of the CHMP’s recommendation.
The marketing authorization application for axicabtagene ciloleucel is supported by data from the ZUMA-1 trial.
Results from this phase 2 trial were presented at the 2017 ASH Annual Meeting and published simultaneously in NEJM.
The trial enrolled 111 patients with relapsed/refractory B-cell lymphomas. There were 101 patients who received axicabtagene ciloleucel—77 with DLBCL, 8 with PMBCL, and 16 with transformed follicular lymphoma (TFL).
Patients received conditioning with low-dose cyclophosphamide and fludarabine, followed by axicabtagene ciloleucel.
The objective response rate (ORR) was 82% (n=83), and the complete response (CR) rate was 54% (n=55).
Among the DLBCL patients, the ORR was 82% (63/77), and the CR rate was 49% (38/77). In the patients with PMBCL or TFL, the ORR was 83% (20/24), and the CR rate was 71% (17/24).
With a median follow-up of 15.4 months, 42% of patients retained their response, and 40% retained a CR.
At 18 months, the overall survival was 52%. Most deaths were due to disease progression.
However, 2 patients died of adverse events related to axicabtagene ciloleucel, both cytokine release syndrome (CRS).
The most common grade 3 or higher adverse events were neutropenia (78%), anemia (43%), thrombocytopenia (38%), and febrile neutropenia (31%).
Grade 3 or higher CRS occurred in 13% of patients, and grade 3 or higher neurologic events occurred in 28%.
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval for the chimeric antigen receptor (CAR) T-cell therapy axicabtagene ciloleucel (Yescarta®, formerly KTE-C19).
The recommendation pertains to axicabtagene ciloleucel as a treatment for adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) or primary mediastinal large B-cell lymphoma (PMBCL) who have received 2 or more lines of systemic therapy.
The CHMP’s recommendation will be reviewed by the European Commission, which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.
The European Commission usually makes a decision within 67 days of the CHMP’s recommendation.
The marketing authorization application for axicabtagene ciloleucel is supported by data from the ZUMA-1 trial.
Results from this phase 2 trial were presented at the 2017 ASH Annual Meeting and published simultaneously in NEJM.
The trial enrolled 111 patients with relapsed/refractory B-cell lymphomas. There were 101 patients who received axicabtagene ciloleucel—77 with DLBCL, 8 with PMBCL, and 16 with transformed follicular lymphoma (TFL).
Patients received conditioning with low-dose cyclophosphamide and fludarabine, followed by axicabtagene ciloleucel.
The objective response rate (ORR) was 82% (n=83), and the complete response (CR) rate was 54% (n=55).
Among the DLBCL patients, the ORR was 82% (63/77), and the CR rate was 49% (38/77). In the patients with PMBCL or TFL, the ORR was 83% (20/24), and the CR rate was 71% (17/24).
With a median follow-up of 15.4 months, 42% of patients retained their response, and 40% retained a CR.
At 18 months, the overall survival was 52%. Most deaths were due to disease progression.
However, 2 patients died of adverse events related to axicabtagene ciloleucel, both cytokine release syndrome (CRS).
The most common grade 3 or higher adverse events were neutropenia (78%), anemia (43%), thrombocytopenia (38%), and febrile neutropenia (31%).
Grade 3 or higher CRS occurred in 13% of patients, and grade 3 or higher neurologic events occurred in 28%.
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval for the chimeric antigen receptor (CAR) T-cell therapy axicabtagene ciloleucel (Yescarta®, formerly KTE-C19).
The recommendation pertains to axicabtagene ciloleucel as a treatment for adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) or primary mediastinal large B-cell lymphoma (PMBCL) who have received 2 or more lines of systemic therapy.
The CHMP’s recommendation will be reviewed by the European Commission, which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.
The European Commission usually makes a decision within 67 days of the CHMP’s recommendation.
The marketing authorization application for axicabtagene ciloleucel is supported by data from the ZUMA-1 trial.
Results from this phase 2 trial were presented at the 2017 ASH Annual Meeting and published simultaneously in NEJM.
The trial enrolled 111 patients with relapsed/refractory B-cell lymphomas. There were 101 patients who received axicabtagene ciloleucel—77 with DLBCL, 8 with PMBCL, and 16 with transformed follicular lymphoma (TFL).
Patients received conditioning with low-dose cyclophosphamide and fludarabine, followed by axicabtagene ciloleucel.
The objective response rate (ORR) was 82% (n=83), and the complete response (CR) rate was 54% (n=55).
Among the DLBCL patients, the ORR was 82% (63/77), and the CR rate was 49% (38/77). In the patients with PMBCL or TFL, the ORR was 83% (20/24), and the CR rate was 71% (17/24).
With a median follow-up of 15.4 months, 42% of patients retained their response, and 40% retained a CR.
At 18 months, the overall survival was 52%. Most deaths were due to disease progression.
However, 2 patients died of adverse events related to axicabtagene ciloleucel, both cytokine release syndrome (CRS).
The most common grade 3 or higher adverse events were neutropenia (78%), anemia (43%), thrombocytopenia (38%), and febrile neutropenia (31%).
Grade 3 or higher CRS occurred in 13% of patients, and grade 3 or higher neurologic events occurred in 28%.
CHMP backs expanded approval of tocilizumab
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended expanding the approved use of tocilizumab (RoActemra).
The recommendation is for tocilizumab to treat adults and pediatric patients age 2 and older who have severe or life-threatening cytokine release syndrome (CRS) induced by chimeric antigen receptor (CAR) T-cell therapy.
The CHMP’s recommendation will be reviewed by the European Commission, which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.
The European Commission usually makes a decision within 67 days of the CHMP’s recommendation.
Tocilizumab is a humanized interleukin-6 receptor antagonist marketed by Roche Registration GmbH.
The drug is already approved by the European Commission to treat rheumatoid arthritis, active systemic juvenile idiopathic arthritis, and juvenile idiopathic polyarthritis.
The CHMP’s recommendation to expand the approved use of tocilizumab is supported by results from a retrospective analysis of data from clinical trials of CAR T-cell therapies in patients with hematologic malignancies.
For this analysis, researchers assessed 45 pediatric and adult patients treated with tocilizumab, with or without additional high-dose corticosteroids, for severe or life-threatening CRS.
Thirty-one patients (69%) achieved a response, defined as resolution of CRS within 14 days of the first dose of tocilizumab.
No more than 2 doses of tocilizumab were needed, and no drugs other than tocilizumab and corticosteroids were used for treatment.
No adverse reactions related to tocilizumab were reported.
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended expanding the approved use of tocilizumab (RoActemra).
The recommendation is for tocilizumab to treat adults and pediatric patients age 2 and older who have severe or life-threatening cytokine release syndrome (CRS) induced by chimeric antigen receptor (CAR) T-cell therapy.
The CHMP’s recommendation will be reviewed by the European Commission, which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.
The European Commission usually makes a decision within 67 days of the CHMP’s recommendation.
Tocilizumab is a humanized interleukin-6 receptor antagonist marketed by Roche Registration GmbH.
The drug is already approved by the European Commission to treat rheumatoid arthritis, active systemic juvenile idiopathic arthritis, and juvenile idiopathic polyarthritis.
The CHMP’s recommendation to expand the approved use of tocilizumab is supported by results from a retrospective analysis of data from clinical trials of CAR T-cell therapies in patients with hematologic malignancies.
For this analysis, researchers assessed 45 pediatric and adult patients treated with tocilizumab, with or without additional high-dose corticosteroids, for severe or life-threatening CRS.
Thirty-one patients (69%) achieved a response, defined as resolution of CRS within 14 days of the first dose of tocilizumab.
No more than 2 doses of tocilizumab were needed, and no drugs other than tocilizumab and corticosteroids were used for treatment.
No adverse reactions related to tocilizumab were reported.
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended expanding the approved use of tocilizumab (RoActemra).
The recommendation is for tocilizumab to treat adults and pediatric patients age 2 and older who have severe or life-threatening cytokine release syndrome (CRS) induced by chimeric antigen receptor (CAR) T-cell therapy.
The CHMP’s recommendation will be reviewed by the European Commission, which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.
The European Commission usually makes a decision within 67 days of the CHMP’s recommendation.
Tocilizumab is a humanized interleukin-6 receptor antagonist marketed by Roche Registration GmbH.
The drug is already approved by the European Commission to treat rheumatoid arthritis, active systemic juvenile idiopathic arthritis, and juvenile idiopathic polyarthritis.
The CHMP’s recommendation to expand the approved use of tocilizumab is supported by results from a retrospective analysis of data from clinical trials of CAR T-cell therapies in patients with hematologic malignancies.
For this analysis, researchers assessed 45 pediatric and adult patients treated with tocilizumab, with or without additional high-dose corticosteroids, for severe or life-threatening CRS.
Thirty-one patients (69%) achieved a response, defined as resolution of CRS within 14 days of the first dose of tocilizumab.
No more than 2 doses of tocilizumab were needed, and no drugs other than tocilizumab and corticosteroids were used for treatment.
No adverse reactions related to tocilizumab were reported.
EC grants blinatumomab full approval
The European Commission (EC) has granted a full marketing authorization for blinatumomab (BLINCYTO®) as a treatment for adults with Philadelphia chromosome-negative (Ph-), relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).
The EC granted blinatumomab conditional authorization for this indication in 2015. Now, the drug has full authorization based on overall survival (OS) data from the phase 3 TOWER study.
This authorization is valid in all European Union and European Economic Area-European Free Trade Association states (Norway, Iceland, and Liechtenstein).
Blinatumomab is a bispecific CD19-directed CD3 T cell engager (BiTE®) immunotherapy construct. It binds to CD19 expressed on the surface of cells of B-lineage origin and CD3 expressed on the surface of effector T cells.
The TOWER study was a phase 3, randomized trial in which researchers compared blinatumomab to standard of care (SOC) chemotherapy in 405 adults with Ph-, relapsed/refractory B-cell precursor ALL.
Patients were randomized in a 2:1 ratio to receive blinatumomab (n=271) or investigator’s choice of SOC chemotherapy (n=134).
On the recommendation of an independent data monitoring committee, Amgen ended the study early for evidence of superior efficacy in the blinatumomab arm.
The median OS was 7.7 months in the blinatumomab arm and 4 months in the SOC arm (hazard ratio=0.71; P=0.012).
For patients treated in first salvage, the median OS was 11.1 months in the blinatumomab arm and 5.3 months in the SOC arm (hazard ratio=0.6).
Safety results in the blinatumomab arm were comparable to those seen in previous phase 2 studies.
These results were published in NEJM in March 2017.
The European Commission (EC) has granted a full marketing authorization for blinatumomab (BLINCYTO®) as a treatment for adults with Philadelphia chromosome-negative (Ph-), relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).
The EC granted blinatumomab conditional authorization for this indication in 2015. Now, the drug has full authorization based on overall survival (OS) data from the phase 3 TOWER study.
This authorization is valid in all European Union and European Economic Area-European Free Trade Association states (Norway, Iceland, and Liechtenstein).
Blinatumomab is a bispecific CD19-directed CD3 T cell engager (BiTE®) immunotherapy construct. It binds to CD19 expressed on the surface of cells of B-lineage origin and CD3 expressed on the surface of effector T cells.
The TOWER study was a phase 3, randomized trial in which researchers compared blinatumomab to standard of care (SOC) chemotherapy in 405 adults with Ph-, relapsed/refractory B-cell precursor ALL.
Patients were randomized in a 2:1 ratio to receive blinatumomab (n=271) or investigator’s choice of SOC chemotherapy (n=134).
On the recommendation of an independent data monitoring committee, Amgen ended the study early for evidence of superior efficacy in the blinatumomab arm.
The median OS was 7.7 months in the blinatumomab arm and 4 months in the SOC arm (hazard ratio=0.71; P=0.012).
For patients treated in first salvage, the median OS was 11.1 months in the blinatumomab arm and 5.3 months in the SOC arm (hazard ratio=0.6).
Safety results in the blinatumomab arm were comparable to those seen in previous phase 2 studies.
These results were published in NEJM in March 2017.
The European Commission (EC) has granted a full marketing authorization for blinatumomab (BLINCYTO®) as a treatment for adults with Philadelphia chromosome-negative (Ph-), relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).
The EC granted blinatumomab conditional authorization for this indication in 2015. Now, the drug has full authorization based on overall survival (OS) data from the phase 3 TOWER study.
This authorization is valid in all European Union and European Economic Area-European Free Trade Association states (Norway, Iceland, and Liechtenstein).
Blinatumomab is a bispecific CD19-directed CD3 T cell engager (BiTE®) immunotherapy construct. It binds to CD19 expressed on the surface of cells of B-lineage origin and CD3 expressed on the surface of effector T cells.
The TOWER study was a phase 3, randomized trial in which researchers compared blinatumomab to standard of care (SOC) chemotherapy in 405 adults with Ph-, relapsed/refractory B-cell precursor ALL.
Patients were randomized in a 2:1 ratio to receive blinatumomab (n=271) or investigator’s choice of SOC chemotherapy (n=134).
On the recommendation of an independent data monitoring committee, Amgen ended the study early for evidence of superior efficacy in the blinatumomab arm.
The median OS was 7.7 months in the blinatumomab arm and 4 months in the SOC arm (hazard ratio=0.71; P=0.012).
For patients treated in first salvage, the median OS was 11.1 months in the blinatumomab arm and 5.3 months in the SOC arm (hazard ratio=0.6).
Safety results in the blinatumomab arm were comparable to those seen in previous phase 2 studies.
These results were published in NEJM in March 2017.
PU-H71 receives orphan drug designation for myelofibrosis
The US Food and Drug Administration (FDA) has granted orphan drug designation to PU-H71 to treat patients with myelofibrosis.
The drug specifically targets the epichaperome, a network of high-molecular-weight complexes found in multiple diseases, including cancer and neurologic disorders. These complexes enhance cellular survival, irrespective of tissue of origin or genetic background.
According to research published in Nature Reviews Cancer, Pu-H71 interferes with the epichaperome function in diseases and does not affect normal cells.
PU-H71 is being evaluated in a phase 1b trial in myelofibrosis and advanced metastatic breast cancer.
“In myelofibrosis, the epichaperome plays a central role in optimizing the JAK-STAT pathway,” said Srdan Verstovsek, MD, PhD, “allowing JAK2 to form dimers that evade inhibition with a JAK2 inhibitor such as ruxolitinib.”
“By inhibiting epichaperome function and breaking this mechanism, we believe PU-H71 can increase anti-cancer activity of JAK2 inhibitors,” he said. Dr Verstovsek, of the MD Anderson Cancer Center in Houston, Texas, is lead clinical research advisor for the phase 1b myelofibrosis study.
Phase 1b Study (NCT01393509)
This is a multicenter study designed to assess the safety, tolerability, pharmacokinetic and preliminary efficacy of PU-H71 in patients taking concomitant ruxolitinib.
The safety expansion phase of the trial is open for accrual only to patients with myeloproliferative neoplasms (MPNs).
These patients must have been on ruxolitinib for at least 3 months, be on a stable dose for at least 1 month prior to enrollment and be taking at least 5 mg twice daily.
Patients must have persistent disease manifestations, despite ruxolitinib therapy. These include persistent splenomegaly, abnormal blood counts, persistent constitutional symptoms, residual fibrosis in bone marrow (2+ or greater), or measurable allele burden as evidenced by clonal JAK2 or MPL mutation.
Samus Therapeutics, the developer of PU-H71, announced, simultaneously with the orphan drug designation, the dosing of the first patient in the phase 1b myelofibrosis study.
“Targeting the epichaperome offers an exciting new avenue for treating myelofibrosis and related diseases,” Dr Verstovsek said.
“I look forward to seeing how the combination of these therapies can affect outcomes in patients for whom this resistance is associated with poor prognoses.”
The US Food and Drug Administration (FDA) has granted orphan drug designation to PU-H71 to treat patients with myelofibrosis.
The drug specifically targets the epichaperome, a network of high-molecular-weight complexes found in multiple diseases, including cancer and neurologic disorders. These complexes enhance cellular survival, irrespective of tissue of origin or genetic background.
According to research published in Nature Reviews Cancer, Pu-H71 interferes with the epichaperome function in diseases and does not affect normal cells.
PU-H71 is being evaluated in a phase 1b trial in myelofibrosis and advanced metastatic breast cancer.
“In myelofibrosis, the epichaperome plays a central role in optimizing the JAK-STAT pathway,” said Srdan Verstovsek, MD, PhD, “allowing JAK2 to form dimers that evade inhibition with a JAK2 inhibitor such as ruxolitinib.”
“By inhibiting epichaperome function and breaking this mechanism, we believe PU-H71 can increase anti-cancer activity of JAK2 inhibitors,” he said. Dr Verstovsek, of the MD Anderson Cancer Center in Houston, Texas, is lead clinical research advisor for the phase 1b myelofibrosis study.
Phase 1b Study (NCT01393509)
This is a multicenter study designed to assess the safety, tolerability, pharmacokinetic and preliminary efficacy of PU-H71 in patients taking concomitant ruxolitinib.
The safety expansion phase of the trial is open for accrual only to patients with myeloproliferative neoplasms (MPNs).
These patients must have been on ruxolitinib for at least 3 months, be on a stable dose for at least 1 month prior to enrollment and be taking at least 5 mg twice daily.
Patients must have persistent disease manifestations, despite ruxolitinib therapy. These include persistent splenomegaly, abnormal blood counts, persistent constitutional symptoms, residual fibrosis in bone marrow (2+ or greater), or measurable allele burden as evidenced by clonal JAK2 or MPL mutation.
Samus Therapeutics, the developer of PU-H71, announced, simultaneously with the orphan drug designation, the dosing of the first patient in the phase 1b myelofibrosis study.
“Targeting the epichaperome offers an exciting new avenue for treating myelofibrosis and related diseases,” Dr Verstovsek said.
“I look forward to seeing how the combination of these therapies can affect outcomes in patients for whom this resistance is associated with poor prognoses.”
The US Food and Drug Administration (FDA) has granted orphan drug designation to PU-H71 to treat patients with myelofibrosis.
The drug specifically targets the epichaperome, a network of high-molecular-weight complexes found in multiple diseases, including cancer and neurologic disorders. These complexes enhance cellular survival, irrespective of tissue of origin or genetic background.
According to research published in Nature Reviews Cancer, Pu-H71 interferes with the epichaperome function in diseases and does not affect normal cells.
PU-H71 is being evaluated in a phase 1b trial in myelofibrosis and advanced metastatic breast cancer.
“In myelofibrosis, the epichaperome plays a central role in optimizing the JAK-STAT pathway,” said Srdan Verstovsek, MD, PhD, “allowing JAK2 to form dimers that evade inhibition with a JAK2 inhibitor such as ruxolitinib.”
“By inhibiting epichaperome function and breaking this mechanism, we believe PU-H71 can increase anti-cancer activity of JAK2 inhibitors,” he said. Dr Verstovsek, of the MD Anderson Cancer Center in Houston, Texas, is lead clinical research advisor for the phase 1b myelofibrosis study.
Phase 1b Study (NCT01393509)
This is a multicenter study designed to assess the safety, tolerability, pharmacokinetic and preliminary efficacy of PU-H71 in patients taking concomitant ruxolitinib.
The safety expansion phase of the trial is open for accrual only to patients with myeloproliferative neoplasms (MPNs).
These patients must have been on ruxolitinib for at least 3 months, be on a stable dose for at least 1 month prior to enrollment and be taking at least 5 mg twice daily.
Patients must have persistent disease manifestations, despite ruxolitinib therapy. These include persistent splenomegaly, abnormal blood counts, persistent constitutional symptoms, residual fibrosis in bone marrow (2+ or greater), or measurable allele burden as evidenced by clonal JAK2 or MPL mutation.
Samus Therapeutics, the developer of PU-H71, announced, simultaneously with the orphan drug designation, the dosing of the first patient in the phase 1b myelofibrosis study.
“Targeting the epichaperome offers an exciting new avenue for treating myelofibrosis and related diseases,” Dr Verstovsek said.
“I look forward to seeing how the combination of these therapies can affect outcomes in patients for whom this resistance is associated with poor prognoses.”
FDA grants pembrolizumab accelerated approval for PMBCL
The US Food and Drug Administration (FDA) granted accelerated approval to the anti-PD-1 therapy pembrolizumab (Keytruda) for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL).
The indication also includes patients who have relapsed after 2 or more prior lines of therapy.
Pembrolizumab had received priority review for PMBCL late last year and also has orphan drug designation and breakthrough therapy designation for this indication.
The FDA based its approval on data from the KEYNOTE-170 (NCT02576990 ) trial.
Investigators enrolled 53 patients onto the multicenter, open-label, single-arm trial. Patients received pembrolizumab 200 mg intravenously every 3 weeks until unacceptable toxicity or documented disease progression.
Patients whose disease did not progress received the drug for up to 24 months.
Patient characteristics
Patients were a median age of 33 years (range, 20 – 61), 43% were male, 92% white, 43% had an ECOG performance status of 0, and 57% had an ECOG performance status of 1.
Almost half (49%) had relapsed disease, and 36% had primary refractory disease.
About a quarter (26%) had undergone prior autologous hematopoietic stem cell transplant, and 32% had prior radiation therapy.
All patients had received prior rituximab.
Results
At a median follow-up of 9.7 months, the overall response rate was 45% (24 responders), including 11% complete responses and 34% partial responses.
The median duration of response was not reached during the follow-up period and ranged from a median 1.1 to 19.2 months.
Median time to first objective response was 2.8 months (range, 2.1 – 8.5). Accordingly, investigators do not recommend pembrolizumab for PMBCL patients who require urgent cytoreductive therapy.
Safety
The most common adverse events occurring in 10% or more of patients were musculoskeletal pain (30%), upper respiratory tract infection (28%), pyrexia (28%), fatigue (23%), cough (26%), dyspnea (21%), diarrhea (13%), abdominal pain (13%), nausea (11%), arrhythmia (11%), and headache (11%).
Eight percent of patients discontinued treatment, and 15% interrupted treatment due to adverse reactions.
Adverse events requiring systemic corticosteroid therapy occurred in 25% of patients.
Serious adverse events occurred in 26% and included arrhythmia (4 %), cardiac tamponade (2%), myocardial infarction (2%), pericardial effusion (2%), and pericarditis (2%).
Six (11%) patients died within 30 days of start of treatment.
The recommended pembrolizumab dose for treatment of adults with PMBCL is 200 mg every 3 weeks. The recommended dose in pediatric patients is 2 mg/kg (up to a maximum of 200 mg) every 3 weeks.
Additional indications for pembrolizumab include melanoma, non-small cell lung cancer, head and neck squamous cell cancer, classical Hodgkin lymphoma, urothelial carcinoma, microsatellite instability-high cancer, gastric cancer, and cervical cancer.
The full prescribing information is available on the FDA website.
Pembrolizumab (Keytruda) is a product of Merck & Co, Inc.
The US Food and Drug Administration (FDA) granted accelerated approval to the anti-PD-1 therapy pembrolizumab (Keytruda) for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL).
The indication also includes patients who have relapsed after 2 or more prior lines of therapy.
Pembrolizumab had received priority review for PMBCL late last year and also has orphan drug designation and breakthrough therapy designation for this indication.
The FDA based its approval on data from the KEYNOTE-170 (NCT02576990 ) trial.
Investigators enrolled 53 patients onto the multicenter, open-label, single-arm trial. Patients received pembrolizumab 200 mg intravenously every 3 weeks until unacceptable toxicity or documented disease progression.
Patients whose disease did not progress received the drug for up to 24 months.
Patient characteristics
Patients were a median age of 33 years (range, 20 – 61), 43% were male, 92% white, 43% had an ECOG performance status of 0, and 57% had an ECOG performance status of 1.
Almost half (49%) had relapsed disease, and 36% had primary refractory disease.
About a quarter (26%) had undergone prior autologous hematopoietic stem cell transplant, and 32% had prior radiation therapy.
All patients had received prior rituximab.
Results
At a median follow-up of 9.7 months, the overall response rate was 45% (24 responders), including 11% complete responses and 34% partial responses.
The median duration of response was not reached during the follow-up period and ranged from a median 1.1 to 19.2 months.
Median time to first objective response was 2.8 months (range, 2.1 – 8.5). Accordingly, investigators do not recommend pembrolizumab for PMBCL patients who require urgent cytoreductive therapy.
Safety
The most common adverse events occurring in 10% or more of patients were musculoskeletal pain (30%), upper respiratory tract infection (28%), pyrexia (28%), fatigue (23%), cough (26%), dyspnea (21%), diarrhea (13%), abdominal pain (13%), nausea (11%), arrhythmia (11%), and headache (11%).
Eight percent of patients discontinued treatment, and 15% interrupted treatment due to adverse reactions.
Adverse events requiring systemic corticosteroid therapy occurred in 25% of patients.
Serious adverse events occurred in 26% and included arrhythmia (4 %), cardiac tamponade (2%), myocardial infarction (2%), pericardial effusion (2%), and pericarditis (2%).
Six (11%) patients died within 30 days of start of treatment.
The recommended pembrolizumab dose for treatment of adults with PMBCL is 200 mg every 3 weeks. The recommended dose in pediatric patients is 2 mg/kg (up to a maximum of 200 mg) every 3 weeks.
Additional indications for pembrolizumab include melanoma, non-small cell lung cancer, head and neck squamous cell cancer, classical Hodgkin lymphoma, urothelial carcinoma, microsatellite instability-high cancer, gastric cancer, and cervical cancer.
The full prescribing information is available on the FDA website.
Pembrolizumab (Keytruda) is a product of Merck & Co, Inc.
The US Food and Drug Administration (FDA) granted accelerated approval to the anti-PD-1 therapy pembrolizumab (Keytruda) for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL).
The indication also includes patients who have relapsed after 2 or more prior lines of therapy.
Pembrolizumab had received priority review for PMBCL late last year and also has orphan drug designation and breakthrough therapy designation for this indication.
The FDA based its approval on data from the KEYNOTE-170 (NCT02576990 ) trial.
Investigators enrolled 53 patients onto the multicenter, open-label, single-arm trial. Patients received pembrolizumab 200 mg intravenously every 3 weeks until unacceptable toxicity or documented disease progression.
Patients whose disease did not progress received the drug for up to 24 months.
Patient characteristics
Patients were a median age of 33 years (range, 20 – 61), 43% were male, 92% white, 43% had an ECOG performance status of 0, and 57% had an ECOG performance status of 1.
Almost half (49%) had relapsed disease, and 36% had primary refractory disease.
About a quarter (26%) had undergone prior autologous hematopoietic stem cell transplant, and 32% had prior radiation therapy.
All patients had received prior rituximab.
Results
At a median follow-up of 9.7 months, the overall response rate was 45% (24 responders), including 11% complete responses and 34% partial responses.
The median duration of response was not reached during the follow-up period and ranged from a median 1.1 to 19.2 months.
Median time to first objective response was 2.8 months (range, 2.1 – 8.5). Accordingly, investigators do not recommend pembrolizumab for PMBCL patients who require urgent cytoreductive therapy.
Safety
The most common adverse events occurring in 10% or more of patients were musculoskeletal pain (30%), upper respiratory tract infection (28%), pyrexia (28%), fatigue (23%), cough (26%), dyspnea (21%), diarrhea (13%), abdominal pain (13%), nausea (11%), arrhythmia (11%), and headache (11%).
Eight percent of patients discontinued treatment, and 15% interrupted treatment due to adverse reactions.
Adverse events requiring systemic corticosteroid therapy occurred in 25% of patients.
Serious adverse events occurred in 26% and included arrhythmia (4 %), cardiac tamponade (2%), myocardial infarction (2%), pericardial effusion (2%), and pericarditis (2%).
Six (11%) patients died within 30 days of start of treatment.
The recommended pembrolizumab dose for treatment of adults with PMBCL is 200 mg every 3 weeks. The recommended dose in pediatric patients is 2 mg/kg (up to a maximum of 200 mg) every 3 weeks.
Additional indications for pembrolizumab include melanoma, non-small cell lung cancer, head and neck squamous cell cancer, classical Hodgkin lymphoma, urothelial carcinoma, microsatellite instability-high cancer, gastric cancer, and cervical cancer.
The full prescribing information is available on the FDA website.
Pembrolizumab (Keytruda) is a product of Merck & Co, Inc.