Preliminary data indicate that a single 32-mg intravenous dose of ondansetron should be avoided because it may increase the risk of QT prolongation, along with the potentially fatal arrhythmia torsades de pointes, the Food and Drug Administration has announced.

GlaxoSmithKline, which manufactures ondansetron (Zofran), is removing the 32-mg single IV dose from the antinausea and vomiting drug’s label, according to an FDA statement.

The updated label will say that ondansetron, a 5-HT₃ receptor antagonist, can continue to be used to treat adults and children with chemotherapy-induced nausea and vomiting at the dose of 0.15 mg/kg administered every 4 hours for three doses. "However, no single intravenous dose of ondansetron should exceed 16 mg due to the risk of QT prolongation," the FDA said.

The new data do not affect recommendations for oral doses of ondansetron (including the single 24-mg oral dose) used for chemotherapy-induced nausea and vomiting, the FDA noted. Recommendations on lower IV doses that are used to prevent postoperative nausea and vomiting (the other approved indication for ondansetron) also are unaffected.

Preliminary results of a study conducted by GlaxoSmithKline showed that QT prolongation "occurs in a dose-dependent manner," the FDA said. At the highest dose tested (the single 32-mg IV dose), the maximum mean difference in QTcF from placebo after baseline-correction was 20 msec. At the lower single dose tested (8 mg), the maximum mean difference in QTcF from placebo after baseline correction was 6 msec.

The FDA, which required GlaxoSmithKline to conduct the study, "will evaluate the final study results when available, and will work with GSK to explore an alternative single dose regimen that is both safe and effective for the prevention of chemotherapy-induced nausea and vomiting in adults," the FDA said.

It pointed out that ECG changes, including QT interval prolongation and torsades de pointes, have been reported in patients treated with ondansetron. In September 2011, the agency announced that it was reviewing the potential for QT prolongation with ondansetron.

Patients who have congenital long QT syndrome, heart failure, or bradyarrhythmias, or who are taking other medications that prolong the QT interval "may be at particular risk for QT prolongation" with ondansetron, the FDA warned.

The statement is available at www.fda.gov/Drugs/DrugSafety/ucm310190.htm. Serious adverse events associated with ondansetron should be reported to the FDA at 800-332-1088 or www.fda.gov/medwatch.

Preliminary data indicate that a single 32-mg intravenous dose of ondansetron should be avoided because it may increase the risk of QT prolongation, along with the potentially fatal arrhythmia torsades de pointes, the Food and Drug Administration has announced.

GlaxoSmithKline, which manufactures ondansetron (Zofran), is removing the 32-mg single IV dose from the antinausea and vomiting drug’s label, according to an FDA statement.

The updated label will say that ondansetron, a 5-HT₃ receptor antagonist, can continue to be used to treat adults and children with chemotherapy-induced nausea and vomiting at the dose of 0.15 mg/kg administered every 4 hours for three doses. "However, no single intravenous dose of ondansetron should exceed 16 mg due to the risk of QT prolongation," the FDA said.

The new data do not affect recommendations for oral doses of ondansetron (including the single 24-mg oral dose) used for chemotherapy-induced nausea and vomiting, the FDA noted. Recommendations on lower IV doses that are used to prevent postoperative nausea and vomiting (the other approved indication for ondansetron) also are unaffected.

Preliminary results of a study conducted by GlaxoSmithKline showed that QT prolongation "occurs in a dose-dependent manner," the FDA said. At the highest dose tested (the single 32-mg IV dose), the maximum mean difference in QTcF from placebo after baseline-correction was 20 msec. At the lower single dose tested (8 mg), the maximum mean difference in QTcF from placebo after baseline correction was 6 msec.

The FDA, which required GlaxoSmithKline to conduct the study, "will evaluate the final study results when available, and will work with GSK to explore an alternative single dose regimen that is both safe and effective for the prevention of chemotherapy-induced nausea and vomiting in adults," the FDA said.

It pointed out that ECG changes, including QT interval prolongation and torsades de pointes, have been reported in patients treated with ondansetron. In September 2011, the agency announced that it was reviewing the potential for QT prolongation with ondansetron.

Patients who have congenital long QT syndrome, heart failure, or bradyarrhythmias, or who are taking other medications that prolong the QT interval "may be at particular risk for QT prolongation" with ondansetron, the FDA warned.

The statement is available at www.fda.gov/Drugs/DrugSafety/ucm310190.htm. Serious adverse events associated with ondansetron should be reported to the FDA at 800-332-1088 or www.fda.gov/medwatch.

Preliminary data indicate that a single 32-mg intravenous dose of ondansetron should be avoided because it may increase the risk of QT prolongation, along with the potentially fatal arrhythmia torsades de pointes, the Food and Drug Administration has announced.

GlaxoSmithKline, which manufactures ondansetron (Zofran), is removing the 32-mg single IV dose from the antinausea and vomiting drug’s label, according to an FDA statement.

The updated label will say that ondansetron, a 5-HT₃ receptor antagonist, can continue to be used to treat adults and children with chemotherapy-induced nausea and vomiting at the dose of 0.15 mg/kg administered every 4 hours for three doses. "However, no single intravenous dose of ondansetron should exceed 16 mg due to the risk of QT prolongation," the FDA said.

The new data do not affect recommendations for oral doses of ondansetron (including the single 24-mg oral dose) used for chemotherapy-induced nausea and vomiting, the FDA noted. Recommendations on lower IV doses that are used to prevent postoperative nausea and vomiting (the other approved indication for ondansetron) also are unaffected.

Preliminary results of a study conducted by GlaxoSmithKline showed that QT prolongation "occurs in a dose-dependent manner," the FDA said. At the highest dose tested (the single 32-mg IV dose), the maximum mean difference in QTcF from placebo after baseline-correction was 20 msec. At the lower single dose tested (8 mg), the maximum mean difference in QTcF from placebo after baseline correction was 6 msec.

The FDA, which required GlaxoSmithKline to conduct the study, "will evaluate the final study results when available, and will work with GSK to explore an alternative single dose regimen that is both safe and effective for the prevention of chemotherapy-induced nausea and vomiting in adults," the FDA said.

It pointed out that ECG changes, including QT interval prolongation and torsades de pointes, have been reported in patients treated with ondansetron. In September 2011, the agency announced that it was reviewing the potential for QT prolongation with ondansetron.

Patients who have congenital long QT syndrome, heart failure, or bradyarrhythmias, or who are taking other medications that prolong the QT interval "may be at particular risk for QT prolongation" with ondansetron, the FDA warned.

The statement is available at www.fda.gov/Drugs/DrugSafety/ucm310190.htm. Serious adverse events associated with ondansetron should be reported to the FDA at 800-332-1088 or www.fda.gov/medwatch.

Three lots of leucovorin calcium injection manufactured by Bedford Laboratories have been recalled because of crystalline particulate matter that is visible in some vials, the Food and Drug Administration announced on July 6.

The nationwide recall applies to lots that were shipped between January and June 2011, and expire in 2013. The particulate matter identified is the active drug substance, according to the FDA and a statement by the company, a division of Ben Venue Laboratories in Bedford, Ohio.

Courtesy of FDA

To date, no foreign matter has been identified, both said, and no adverse reactions have been reported in association with any of the recalled lots.

Particulate matter is considered a potential health hazard in that it can case vein irritation and phlebitis, clinically occult pulmonary granulomas, local tissue infarction, severe pulmonary dysfunction, occlusion of capillaries and arteries, anaphylactic shock, and death, according to the FDA and Bedford.

Leucovorin is widely used in oncology, with indications for rescue after high-dose methotrexate administration in osteosarcoma as well as to counteract methotrexate toxicity, impaired methotrexate elimination, and inadvertent overdoses of folic acid antagonists. It is also indicated in the treatment of megaloblastic anemias caused by folic acid deficiency, when oral therapy is not feasible; and in combination with 5-fluorouracil in patients with advanced colorectal cancer.

Leucovorin is one of the generic cancer drugs in short supply, according to an FDA listing of current drug shortages. Bedford Laboratories cited "manufacturing delays" for the limited availability of its leucovorin products in an entry last updated April 10, 2012.

Lot numbers of the recalled products are: 2017620, 2038374, and 2038374A. Health care practitioners are advised to quarantine recalled vials for return to the company.

Adverse reactions associated with the recalled leucovorin lots should be reported to the manufacturer at 800-521-5169 or the FDA at 800-332-1088 or www.fda.gov/medwatch.

Three lots of leucovorin calcium injection manufactured by Bedford Laboratories have been recalled because of crystalline particulate matter that is visible in some vials, the Food and Drug Administration announced on July 6.

The nationwide recall applies to lots that were shipped between January and June 2011, and expire in 2013. The particulate matter identified is the active drug substance, according to the FDA and a statement by the company, a division of Ben Venue Laboratories in Bedford, Ohio.

Courtesy of FDA

To date, no foreign matter has been identified, both said, and no adverse reactions have been reported in association with any of the recalled lots.

Particulate matter is considered a potential health hazard in that it can case vein irritation and phlebitis, clinically occult pulmonary granulomas, local tissue infarction, severe pulmonary dysfunction, occlusion of capillaries and arteries, anaphylactic shock, and death, according to the FDA and Bedford.

Leucovorin is widely used in oncology, with indications for rescue after high-dose methotrexate administration in osteosarcoma as well as to counteract methotrexate toxicity, impaired methotrexate elimination, and inadvertent overdoses of folic acid antagonists. It is also indicated in the treatment of megaloblastic anemias caused by folic acid deficiency, when oral therapy is not feasible; and in combination with 5-fluorouracil in patients with advanced colorectal cancer.

Leucovorin is one of the generic cancer drugs in short supply, according to an FDA listing of current drug shortages. Bedford Laboratories cited "manufacturing delays" for the limited availability of its leucovorin products in an entry last updated April 10, 2012.

Lot numbers of the recalled products are: 2017620, 2038374, and 2038374A. Health care practitioners are advised to quarantine recalled vials for return to the company.

Adverse reactions associated with the recalled leucovorin lots should be reported to the manufacturer at 800-521-5169 or the FDA at 800-332-1088 or www.fda.gov/medwatch.

Three lots of leucovorin calcium injection manufactured by Bedford Laboratories have been recalled because of crystalline particulate matter that is visible in some vials, the Food and Drug Administration announced on July 6.

The nationwide recall applies to lots that were shipped between January and June 2011, and expire in 2013. The particulate matter identified is the active drug substance, according to the FDA and a statement by the company, a division of Ben Venue Laboratories in Bedford, Ohio.

Courtesy of FDA

To date, no foreign matter has been identified, both said, and no adverse reactions have been reported in association with any of the recalled lots.

Particulate matter is considered a potential health hazard in that it can case vein irritation and phlebitis, clinically occult pulmonary granulomas, local tissue infarction, severe pulmonary dysfunction, occlusion of capillaries and arteries, anaphylactic shock, and death, according to the FDA and Bedford.

Leucovorin is widely used in oncology, with indications for rescue after high-dose methotrexate administration in osteosarcoma as well as to counteract methotrexate toxicity, impaired methotrexate elimination, and inadvertent overdoses of folic acid antagonists. It is also indicated in the treatment of megaloblastic anemias caused by folic acid deficiency, when oral therapy is not feasible; and in combination with 5-fluorouracil in patients with advanced colorectal cancer.

Leucovorin is one of the generic cancer drugs in short supply, according to an FDA listing of current drug shortages. Bedford Laboratories cited "manufacturing delays" for the limited availability of its leucovorin products in an entry last updated April 10, 2012.

Lot numbers of the recalled products are: 2017620, 2038374, and 2038374A. Health care practitioners are advised to quarantine recalled vials for return to the company.

Adverse reactions associated with the recalled leucovorin lots should be reported to the manufacturer at 800-521-5169 or the FDA at 800-332-1088 or www.fda.gov/medwatch.

AMSTERDAM – Up to 43% of elderly patients with diffuse large B cell lymphoma might be spared radiotherapy for bulky disease, if research suggesting that there is no additional benefit when using a standard chemotherapy regimen is confirmed.

In a prospective study from Germany, patients who achieved a complete remission (CR) or complete remission unconfirmed (CRu) with R-CHOP-14 plus two subsequent doses of rituximab (Rituxan) gained no additional benefit in event-free survival (EFS), progression-free survival (PFS), or overall survival (OS), compared with a historical prospective cohort.

Sara Freeman/IMNG Medical Media

However, patients who did not achieve a CR/CRu following the chemotherapy did appear to benefit from radiotherapy to bulky disease, with higher rates on all three measures in the RICOVER-60-No-Rx trial, a German High Grade Non-Hodgkin’s Lymphoma Study Group (DSHNHL) trial,

"The role of radiotherapy in the treatment of aggressive non-Hodgkin’s lymphoma is rather unclear, especially in the rituximab era, where systemic chemotherapy has become highly effective," Dr. Gerhard Held said at the annual congress of the European Hematology Association.

"The question arises if a local therapeutic modality like radiotherapy provides benefit to patients or [if it is] just adding additional toxicity," Dr. Held of Saarland University Hospital, Homburg, Germany, added.

The RICOVER-60-No-Rx trial resulted from a protocol amendment of the previously reported RICOVER-60 trial conducted in elderly patients with diffuse large B-cell lymphoma (DLBCL). The latter involved more than 1,200 men and women with DLBCL who were aged 61-80 years.

RICOVER-60 had a 2x2 factorial design and compared six or eight cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone given for 14 days (CHOP-14) with or without additional rituximab (R-CHOP-14). Patients with extranodal or bulky disease, defined as a tumor of more than 7.5 cm in diameter, received additional involved-field radiotherapy of 36 Gy.

The trial’s results (Lancet Oncol. 2008;9:105-16) showed a clear benefit of adding rituximab to the CHOP-14 regimen. The aim of the RICOVER-60-No-Rx study was to look more specifically at the role of radiotherapy in patients who had received the chemotherapy regimen.

In total 166 patients received additional chemotherapy without radiotherapy after the protocol amendment, and outcome data on these patients were compared with data on 306 patients who had received R-CHOP-14 plus two additional doses of rituximab and radiotherapy to bulky disease in the RICOVER-60 trial.

Dr. Held reported that, compared with the RICOVER-60 population, those in the RICOVER-60-No-Rx trial were older (median age of 69 vs. 71 years, P = .018), more likely to have advanced (stage III/IV) disease (50% vs. 60%, P = .037), and have extranodal involvement (50% vs. 63%, P = .024). In contrast, patients in the RICOVER-60 study were more likely to have bulky disease (35 vs. 29%, P = .024).

After a median observation time of 39 months, EFS (80% vs. 54%; P = .001), PFS (88% vs. 62%; P less than .001), and OS (90% vs. 65%; P = .001) were initially higher when comparing the RICOVER-60 cohort with the RICOVER-No-Rx cohort. However, taking protocol violations and the differences in demographics into consideration, there was no difference in the three measures between the groups overall (3-year EFS and PFS: 84% vs. 75%; P = .430); OS (87% vs. 79%; P = .839). Only patients who had not adequately responded to R-CHOP 14 appeared to benefit.

This was a not a randomized investigation, Dr. Held noted, and so of course further clarification of the role of radiotherapy in DCLBL is needed. To that end, the DSHNHL UNFOLDER trial is underway; this trial is looking look at the use of radiotherapy to bulky lesions vs. observation after six cycles of treatment with R-CHOP-14 or R-CHOP 21.

Computed tomography rather than positron emission tomography was used to stage patients, Dr. Aaron Polliack, emeritus professor of hematology and former head of the lymphoma and leukemia unit at Hadassah University Hospital in Jerusalem, noted during discussion that followed.

The results of the current trial therefore warrant caution in their interpretation, suggested Dr. Polliack, who is editor in chief of the journal Leukemia and Lymphoma and not involved in the study. He further commented that no decision can truly be made on the value of radiotherapy in this clinical situation until further data from the UNFOLDER and other studies are available.

The RICOVER-60-No-Rx trial was supported by Deutsche Krebshilfe and the original RICOVER-60 trial by Roche. Dr. Held disclosed receiving travel grants from Roche. Dr. Polliack had no conflicts of interest.

AMSTERDAM – Up to 43% of elderly patients with diffuse large B cell lymphoma might be spared radiotherapy for bulky disease, if research suggesting that there is no additional benefit when using a standard chemotherapy regimen is confirmed.

In a prospective study from Germany, patients who achieved a complete remission (CR) or complete remission unconfirmed (CRu) with R-CHOP-14 plus two subsequent doses of rituximab (Rituxan) gained no additional benefit in event-free survival (EFS), progression-free survival (PFS), or overall survival (OS), compared with a historical prospective cohort.

Sara Freeman/IMNG Medical Media

However, patients who did not achieve a CR/CRu following the chemotherapy did appear to benefit from radiotherapy to bulky disease, with higher rates on all three measures in the RICOVER-60-No-Rx trial, a German High Grade Non-Hodgkin’s Lymphoma Study Group (DSHNHL) trial,

"The role of radiotherapy in the treatment of aggressive non-Hodgkin’s lymphoma is rather unclear, especially in the rituximab era, where systemic chemotherapy has become highly effective," Dr. Gerhard Held said at the annual congress of the European Hematology Association.

"The question arises if a local therapeutic modality like radiotherapy provides benefit to patients or [if it is] just adding additional toxicity," Dr. Held of Saarland University Hospital, Homburg, Germany, added.

The RICOVER-60-No-Rx trial resulted from a protocol amendment of the previously reported RICOVER-60 trial conducted in elderly patients with diffuse large B-cell lymphoma (DLBCL). The latter involved more than 1,200 men and women with DLBCL who were aged 61-80 years.

RICOVER-60 had a 2x2 factorial design and compared six or eight cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone given for 14 days (CHOP-14) with or without additional rituximab (R-CHOP-14). Patients with extranodal or bulky disease, defined as a tumor of more than 7.5 cm in diameter, received additional involved-field radiotherapy of 36 Gy.

The trial’s results (Lancet Oncol. 2008;9:105-16) showed a clear benefit of adding rituximab to the CHOP-14 regimen. The aim of the RICOVER-60-No-Rx study was to look more specifically at the role of radiotherapy in patients who had received the chemotherapy regimen.

In total 166 patients received additional chemotherapy without radiotherapy after the protocol amendment, and outcome data on these patients were compared with data on 306 patients who had received R-CHOP-14 plus two additional doses of rituximab and radiotherapy to bulky disease in the RICOVER-60 trial.

Dr. Held reported that, compared with the RICOVER-60 population, those in the RICOVER-60-No-Rx trial were older (median age of 69 vs. 71 years, P = .018), more likely to have advanced (stage III/IV) disease (50% vs. 60%, P = .037), and have extranodal involvement (50% vs. 63%, P = .024). In contrast, patients in the RICOVER-60 study were more likely to have bulky disease (35 vs. 29%, P = .024).

After a median observation time of 39 months, EFS (80% vs. 54%; P = .001), PFS (88% vs. 62%; P less than .001), and OS (90% vs. 65%; P = .001) were initially higher when comparing the RICOVER-60 cohort with the RICOVER-No-Rx cohort. However, taking protocol violations and the differences in demographics into consideration, there was no difference in the three measures between the groups overall (3-year EFS and PFS: 84% vs. 75%; P = .430); OS (87% vs. 79%; P = .839). Only patients who had not adequately responded to R-CHOP 14 appeared to benefit.

This was a not a randomized investigation, Dr. Held noted, and so of course further clarification of the role of radiotherapy in DCLBL is needed. To that end, the DSHNHL UNFOLDER trial is underway; this trial is looking look at the use of radiotherapy to bulky lesions vs. observation after six cycles of treatment with R-CHOP-14 or R-CHOP 21.

Computed tomography rather than positron emission tomography was used to stage patients, Dr. Aaron Polliack, emeritus professor of hematology and former head of the lymphoma and leukemia unit at Hadassah University Hospital in Jerusalem, noted during discussion that followed.

The results of the current trial therefore warrant caution in their interpretation, suggested Dr. Polliack, who is editor in chief of the journal Leukemia and Lymphoma and not involved in the study. He further commented that no decision can truly be made on the value of radiotherapy in this clinical situation until further data from the UNFOLDER and other studies are available.

The RICOVER-60-No-Rx trial was supported by Deutsche Krebshilfe and the original RICOVER-60 trial by Roche. Dr. Held disclosed receiving travel grants from Roche. Dr. Polliack had no conflicts of interest.

AMSTERDAM – Up to 43% of elderly patients with diffuse large B cell lymphoma might be spared radiotherapy for bulky disease, if research suggesting that there is no additional benefit when using a standard chemotherapy regimen is confirmed.

In a prospective study from Germany, patients who achieved a complete remission (CR) or complete remission unconfirmed (CRu) with R-CHOP-14 plus two subsequent doses of rituximab (Rituxan) gained no additional benefit in event-free survival (EFS), progression-free survival (PFS), or overall survival (OS), compared with a historical prospective cohort.

Sara Freeman/IMNG Medical Media

However, patients who did not achieve a CR/CRu following the chemotherapy did appear to benefit from radiotherapy to bulky disease, with higher rates on all three measures in the RICOVER-60-No-Rx trial, a German High Grade Non-Hodgkin’s Lymphoma Study Group (DSHNHL) trial,

"The role of radiotherapy in the treatment of aggressive non-Hodgkin’s lymphoma is rather unclear, especially in the rituximab era, where systemic chemotherapy has become highly effective," Dr. Gerhard Held said at the annual congress of the European Hematology Association.

"The question arises if a local therapeutic modality like radiotherapy provides benefit to patients or [if it is] just adding additional toxicity," Dr. Held of Saarland University Hospital, Homburg, Germany, added.

The RICOVER-60-No-Rx trial resulted from a protocol amendment of the previously reported RICOVER-60 trial conducted in elderly patients with diffuse large B-cell lymphoma (DLBCL). The latter involved more than 1,200 men and women with DLBCL who were aged 61-80 years.

RICOVER-60 had a 2x2 factorial design and compared six or eight cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone given for 14 days (CHOP-14) with or without additional rituximab (R-CHOP-14). Patients with extranodal or bulky disease, defined as a tumor of more than 7.5 cm in diameter, received additional involved-field radiotherapy of 36 Gy.

The trial’s results (Lancet Oncol. 2008;9:105-16) showed a clear benefit of adding rituximab to the CHOP-14 regimen. The aim of the RICOVER-60-No-Rx study was to look more specifically at the role of radiotherapy in patients who had received the chemotherapy regimen.

In total 166 patients received additional chemotherapy without radiotherapy after the protocol amendment, and outcome data on these patients were compared with data on 306 patients who had received R-CHOP-14 plus two additional doses of rituximab and radiotherapy to bulky disease in the RICOVER-60 trial.

Dr. Held reported that, compared with the RICOVER-60 population, those in the RICOVER-60-No-Rx trial were older (median age of 69 vs. 71 years, P = .018), more likely to have advanced (stage III/IV) disease (50% vs. 60%, P = .037), and have extranodal involvement (50% vs. 63%, P = .024). In contrast, patients in the RICOVER-60 study were more likely to have bulky disease (35 vs. 29%, P = .024).

After a median observation time of 39 months, EFS (80% vs. 54%; P = .001), PFS (88% vs. 62%; P less than .001), and OS (90% vs. 65%; P = .001) were initially higher when comparing the RICOVER-60 cohort with the RICOVER-No-Rx cohort. However, taking protocol violations and the differences in demographics into consideration, there was no difference in the three measures between the groups overall (3-year EFS and PFS: 84% vs. 75%; P = .430); OS (87% vs. 79%; P = .839). Only patients who had not adequately responded to R-CHOP 14 appeared to benefit.

This was a not a randomized investigation, Dr. Held noted, and so of course further clarification of the role of radiotherapy in DCLBL is needed. To that end, the DSHNHL UNFOLDER trial is underway; this trial is looking look at the use of radiotherapy to bulky lesions vs. observation after six cycles of treatment with R-CHOP-14 or R-CHOP 21.

Computed tomography rather than positron emission tomography was used to stage patients, Dr. Aaron Polliack, emeritus professor of hematology and former head of the lymphoma and leukemia unit at Hadassah University Hospital in Jerusalem, noted during discussion that followed.

The results of the current trial therefore warrant caution in their interpretation, suggested Dr. Polliack, who is editor in chief of the journal Leukemia and Lymphoma and not involved in the study. He further commented that no decision can truly be made on the value of radiotherapy in this clinical situation until further data from the UNFOLDER and other studies are available.

The RICOVER-60-No-Rx trial was supported by Deutsche Krebshilfe and the original RICOVER-60 trial by Roche. Dr. Held disclosed receiving travel grants from Roche. Dr. Polliack had no conflicts of interest.

SILVER SPRING, MD. – Carfilzomib, a second-generation proteasome inhibitor studied in patients with relapsed and refractory multiple myeloma, overcame concerns about cardiotoxicity to win a Food and Drug Administration advisory panel’s support for accelerated approval.

The Oncologic Drugs Advisory Committee (ODAC) voted 11 to 0 with 1 abstention that carfilzomib’s risk-benefit profile is favorable for patients with relapsed and refractory multiple myeloma, who have received at least two prior lines of therapy that included a proteasome inhibitor and an immunomodulatory drug (IMiD) – the indication under review.

If the FDA approves carfilzomib, the manufacturer, Onyx Pharmaceuticals Inc., plans to market the new drug as Kyprolis. It would be the second proteasome inhibitor for multiple myeloma. Bortezomib (Velcade) was approved in 2003, and has had an important role in prolonging the lives of patients with this cancer.

The proposed indication is based on the results of a single-arm phase II study conducted in the United States and Canada. The open label trial enrolled 266 patients who had relapsed or refractory disease and had received at least two prior lines of therapy, including a proteasome inhibitor and an IMiD – either thalidomide or lenalidomide (Revlimid).

Patients started on carfilzomib a median of 5.4 years after they were initially diagnosed; their median age was 63 years. The investigational drug was administered twice weekly for 3 weeks followed by a rest period in a 28-day cycle.

The overall response rate (complete response, very good partial response, and partial responses combined) was 22.9%, in the intent-to-treat population, and the median duration of response was 7.8 months. Though most responses were partial (18%), one patient had a complete response.

Serious toxicities included seven cardiac deaths and a smaller number of life-threatening pulmonary and hepatic adverse events, but it was not clear what role the disease, previous therapies, or carfilzomib had on the adverse event profile, according to the FDA reviewer.

Onyx cited the lack of alternatives for patients who have exhausted all treatment options for multiple myeloma, the "meaningful and durable response" seen in the study, and the well characterized safety profile among reasons that justified an accelerated approval.

Noting that these patients had end-stage multiple myeloma with few, if any, available treatment options, ODAC panelists agreed that the response rate and safety profile observed in the phase II study were acceptable and justified an accelerated approval. ODAC members were also encouraged by the fact that enrollment in a phase III confirmatory trial of carfilzomib, a requirement for drugs that receive accelerated approval, has already been completed.

There is an unmet need for this group of patients, who have run out of options, and the study outcome "is a signal that I believe will be confirmed in clinical trials," said ODAC’s chair, Dr. Wyndham Wilson.

Cardiotoxicity is not a major concern when considering that these heavily pretreated patients had already been exposed to considerable toxicity, said Dr. Wilson, chair of the lymphoma therapeutics section in the metabolism branch of the Center for Cancer Research at the National Cancer Institute. Everything has to be put into context, he said.

"The responses are real and even more importantly, are meaningful in this population," said panelist Dr. Deborah Armstrong of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins in Baltimore. Considering what is currently available for these patients, carfilzomib "definitely improves the therapeutic armamentarium" for this population, she added.

Onyx issued a statement immediately after the vote saying it "is committed to bringing Kyprolis to patients as quickly as possible and looks forward to working closely with the FDA as the agency completes its review." The agency must act on the new drug application by July 27, it noted.

In addition, the company hinted that earlier indications will be sought; "Onyx is developing Kyprolis for use in multiple myeloma across a variety of treatment lines," according to the statement.

As a condition of accelerated approval, manufacturers are required to confirm the efficacy and safety of drugs in phase III studies. If those studies fail to confirm the results of the phase II study, the FDA can withdraw approval.

The FDA usually follows the recommendations of its advisory panels, which are not binding. ODAC members were cleared of potential conflicts of interest before the meeting.

SILVER SPRING, MD. – Carfilzomib, a second-generation proteasome inhibitor studied in patients with relapsed and refractory multiple myeloma, overcame concerns about cardiotoxicity to win a Food and Drug Administration advisory panel’s support for accelerated approval.

The Oncologic Drugs Advisory Committee (ODAC) voted 11 to 0 with 1 abstention that carfilzomib’s risk-benefit profile is favorable for patients with relapsed and refractory multiple myeloma, who have received at least two prior lines of therapy that included a proteasome inhibitor and an immunomodulatory drug (IMiD) – the indication under review.

If the FDA approves carfilzomib, the manufacturer, Onyx Pharmaceuticals Inc., plans to market the new drug as Kyprolis. It would be the second proteasome inhibitor for multiple myeloma. Bortezomib (Velcade) was approved in 2003, and has had an important role in prolonging the lives of patients with this cancer.

The proposed indication is based on the results of a single-arm phase II study conducted in the United States and Canada. The open label trial enrolled 266 patients who had relapsed or refractory disease and had received at least two prior lines of therapy, including a proteasome inhibitor and an IMiD – either thalidomide or lenalidomide (Revlimid).

Patients started on carfilzomib a median of 5.4 years after they were initially diagnosed; their median age was 63 years. The investigational drug was administered twice weekly for 3 weeks followed by a rest period in a 28-day cycle.

The overall response rate (complete response, very good partial response, and partial responses combined) was 22.9%, in the intent-to-treat population, and the median duration of response was 7.8 months. Though most responses were partial (18%), one patient had a complete response.

Serious toxicities included seven cardiac deaths and a smaller number of life-threatening pulmonary and hepatic adverse events, but it was not clear what role the disease, previous therapies, or carfilzomib had on the adverse event profile, according to the FDA reviewer.

Onyx cited the lack of alternatives for patients who have exhausted all treatment options for multiple myeloma, the "meaningful and durable response" seen in the study, and the well characterized safety profile among reasons that justified an accelerated approval.

Noting that these patients had end-stage multiple myeloma with few, if any, available treatment options, ODAC panelists agreed that the response rate and safety profile observed in the phase II study were acceptable and justified an accelerated approval. ODAC members were also encouraged by the fact that enrollment in a phase III confirmatory trial of carfilzomib, a requirement for drugs that receive accelerated approval, has already been completed.

There is an unmet need for this group of patients, who have run out of options, and the study outcome "is a signal that I believe will be confirmed in clinical trials," said ODAC’s chair, Dr. Wyndham Wilson.

Cardiotoxicity is not a major concern when considering that these heavily pretreated patients had already been exposed to considerable toxicity, said Dr. Wilson, chair of the lymphoma therapeutics section in the metabolism branch of the Center for Cancer Research at the National Cancer Institute. Everything has to be put into context, he said.

"The responses are real and even more importantly, are meaningful in this population," said panelist Dr. Deborah Armstrong of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins in Baltimore. Considering what is currently available for these patients, carfilzomib "definitely improves the therapeutic armamentarium" for this population, she added.

Onyx issued a statement immediately after the vote saying it "is committed to bringing Kyprolis to patients as quickly as possible and looks forward to working closely with the FDA as the agency completes its review." The agency must act on the new drug application by July 27, it noted.

In addition, the company hinted that earlier indications will be sought; "Onyx is developing Kyprolis for use in multiple myeloma across a variety of treatment lines," according to the statement.

As a condition of accelerated approval, manufacturers are required to confirm the efficacy and safety of drugs in phase III studies. If those studies fail to confirm the results of the phase II study, the FDA can withdraw approval.

The FDA usually follows the recommendations of its advisory panels, which are not binding. ODAC members were cleared of potential conflicts of interest before the meeting.

SILVER SPRING, MD. – Carfilzomib, a second-generation proteasome inhibitor studied in patients with relapsed and refractory multiple myeloma, overcame concerns about cardiotoxicity to win a Food and Drug Administration advisory panel’s support for accelerated approval.

The Oncologic Drugs Advisory Committee (ODAC) voted 11 to 0 with 1 abstention that carfilzomib’s risk-benefit profile is favorable for patients with relapsed and refractory multiple myeloma, who have received at least two prior lines of therapy that included a proteasome inhibitor and an immunomodulatory drug (IMiD) – the indication under review.

If the FDA approves carfilzomib, the manufacturer, Onyx Pharmaceuticals Inc., plans to market the new drug as Kyprolis. It would be the second proteasome inhibitor for multiple myeloma. Bortezomib (Velcade) was approved in 2003, and has had an important role in prolonging the lives of patients with this cancer.

The proposed indication is based on the results of a single-arm phase II study conducted in the United States and Canada. The open label trial enrolled 266 patients who had relapsed or refractory disease and had received at least two prior lines of therapy, including a proteasome inhibitor and an IMiD – either thalidomide or lenalidomide (Revlimid).

Patients started on carfilzomib a median of 5.4 years after they were initially diagnosed; their median age was 63 years. The investigational drug was administered twice weekly for 3 weeks followed by a rest period in a 28-day cycle.

The overall response rate (complete response, very good partial response, and partial responses combined) was 22.9%, in the intent-to-treat population, and the median duration of response was 7.8 months. Though most responses were partial (18%), one patient had a complete response.

Serious toxicities included seven cardiac deaths and a smaller number of life-threatening pulmonary and hepatic adverse events, but it was not clear what role the disease, previous therapies, or carfilzomib had on the adverse event profile, according to the FDA reviewer.

Onyx cited the lack of alternatives for patients who have exhausted all treatment options for multiple myeloma, the "meaningful and durable response" seen in the study, and the well characterized safety profile among reasons that justified an accelerated approval.

Noting that these patients had end-stage multiple myeloma with few, if any, available treatment options, ODAC panelists agreed that the response rate and safety profile observed in the phase II study were acceptable and justified an accelerated approval. ODAC members were also encouraged by the fact that enrollment in a phase III confirmatory trial of carfilzomib, a requirement for drugs that receive accelerated approval, has already been completed.

There is an unmet need for this group of patients, who have run out of options, and the study outcome "is a signal that I believe will be confirmed in clinical trials," said ODAC’s chair, Dr. Wyndham Wilson.

Cardiotoxicity is not a major concern when considering that these heavily pretreated patients had already been exposed to considerable toxicity, said Dr. Wilson, chair of the lymphoma therapeutics section in the metabolism branch of the Center for Cancer Research at the National Cancer Institute. Everything has to be put into context, he said.

"The responses are real and even more importantly, are meaningful in this population," said panelist Dr. Deborah Armstrong of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins in Baltimore. Considering what is currently available for these patients, carfilzomib "definitely improves the therapeutic armamentarium" for this population, she added.

Onyx issued a statement immediately after the vote saying it "is committed to bringing Kyprolis to patients as quickly as possible and looks forward to working closely with the FDA as the agency completes its review." The agency must act on the new drug application by July 27, it noted.

In addition, the company hinted that earlier indications will be sought; "Onyx is developing Kyprolis for use in multiple myeloma across a variety of treatment lines," according to the statement.

As a condition of accelerated approval, manufacturers are required to confirm the efficacy and safety of drugs in phase III studies. If those studies fail to confirm the results of the phase II study, the FDA can withdraw approval.

The FDA usually follows the recommendations of its advisory panels, which are not binding. ODAC members were cleared of potential conflicts of interest before the meeting.

Serious cardiac, pulmonary, and hepatic toxicities associated with Onyx Pharmaceuticals Inc.’s investigational multiple myeloma drug Kyprolis (carfilzomib) may outweigh its benefits in a patient population that has not been shown to be refractory or intolerant to all available treatments, the Food and Drug Administration announced.

In briefing documents released ahead of the Oncologic Drugs Advisory Committee’s June 20 review of carfilzomib, the FDA said it is "very concerned" with the severe toxicities associated with the second-generation proteasome inhibitor and questions whether it is possible to identify patients at high risk for life-threatening, drug-related toxicities.

The agency also questions whether a lone, single-arm phase II trial provides sufficient evidence demonstrating that carfilzomib is beneficial over other available therapies in a relapsed/refractory population. Only a minority of all patients in the study were shown to be unresponsive or intolerant to most of the existing approved treatments for multiple myeloma.

The FDA seeks an ODAC vote on whether carfilzomib’s risk/benefit assessment is favorable for the indication requested. In considering this question, the committee will have to weigh whether accelerated approval is justified now, or whether an approval decision should await data from ongoing phase III trials that are expected to provide more clarity on the drug’s safety and efficacy profile in the relapsed/refractory setting.

Benefit Over Existing Therapies

Onyx is seeking carfilzomib’s approval for treatment of patients with relapsed and refractory multiple myeloma who have received at least two prior lines of therapy that included a proteasome inhibitor and an immunomodulatory agent. The NDA seeking accelerated approval was submitted in September 2011. The FDA denied Onyx’s request for priority review; the user fee goal date under a 10-month standard review is July 27.

The FDA’s briefing documents released on June 18 seek to put carfilzomib’s proposed use into the context of the seven drugs across five classes that are currently approved for treating multiple myeloma. Onyx is seeking approval based upon the results of Study PX-171-003 Part 2 (Study 3), a single-arm, phase II study of 266 patients. Subjects were required to have received prior treatment with bortezomib and either thalidomide or lenalidomide. They also must have received an alkylating agent, either alone or in combination with other multiple myeloma treatments, and an anthracycline, either alone or in combination with other treatments unless not clinically indicated.

The agency’s review notes that accelerated approval is a regulatory pathway for drugs that treat serious or life-threatening illnesses and that provide meaningful therapeutic benefit to patients over existing treatments. "Therefore, it is important to analyze the prior treatment history of each patient entered onto the primary efficacy phase II study (Study 3), and to determine whether each patient had been documented to be unresponsive to or intolerant of each of the drugs which have been approved by the FDA as therapy for multiple myeloma," the FDA said.

"Of the 266 patients enrolled in the study, 35.7% never received anthracyclines, 34.2% never received cyclophosphamide, 15.4% never received melphalan, and only 1.9% of patients were exposed to carmustine," the FDA said. Although 86.8% of patients were documented to be unresponsive or intolerant to both bortezomib and lenalidomide, only 56% were shown to be unresponsive or intolerant to thalidomide. Less than half were shown to be unresponsive or intolerant to anthracyclines (36.8%), cyclophosphamide (34.6%), or melphalan (28.9%).

The trial’s primary end point was overall response rate, as assessed by an independent review committee. The sponsor’s reported ORR was 22.9% in the intent-to-treat population. The FDA analyzed the results according to therapies for which patients were unresponsive or intolerant, and the ORR in these groups ranged from 20.2% to 23.2%.

The sponsor reported a median duration of response of 7.8 months; the FDA used a different definition to calculate duration of response and came up with a median of 6.5 months.

The agency suggested the efficacy results may have been confounded by concomitant use of the steroid dexamethasone in all subjects to reduce transfusion-related reactions. Dexamethasone is routinely given either alone or with other therapies to treat patients with multiple myeloma, the FDA pointed out. Although the dose given in Study 3 was lower than the amount typically given, "a therapeutic effect cannot be ruled out in a single-arm trial. In Study 3, the actual treatment effect of carfilzomib is confounded by the concomitant use of dexamethasone in the study and the response rates may be lower in the absence of steroids."

Deaths, SAEs, and Discontinuations

There were a total of 24 on-study deaths in the trial. Although disease progression accounted for half of these, as many as nine others were directly or possibly related to cardiac causes, the FDA said, and two deaths were blamed on hepatic failure.

Across the 526 multiple myeloma patients enrolled in phase II studies, 8% experienced a cardiac serious adverse event (SAE), and 7% experienced pulmonary toxicity. The majority of these serious adverse events were grade 3 or 4 toxicities. The most frequent cardiac SAEs were heart failure and cardiac arrest. Major adverse events leading to carfilzomib discontinuation across the phase II trials were dyspnea, pneumonia, and heart failure.

The FDA noted that determining whether adverse events are drug related can be problematic in the setting of single-arm trials.

"In general, the cause of adverse events from single-arm trials where the drug effect is unknown must be assigned to the experimental therapy," the FDA said. "Among the safety population of patients with multiple myeloma enrolled in phase II studies, there are several organ systems in which a higher incidence of adverse events has occurred than would be expected in this population of patients with multiple myeloma including cardiac, pulmonary, and hepatic toxicities, which must be assigned to carfilzomib. In addition to significant life-threatening adverse events associated with the heart, lung, and liver, a separate and distinct set of adverse events was associated with the infusion of carfilzomib."

Multiple myeloma patients treated with immunomodulatory agents do not show this pattern of cardiac, pulmonary, and hepatic toxicities, the FDA said. The agency also noted that cardiac and pulmonary toxicities, among others, were seen in preclinical studies of carfilzomib, although the pathogenesis of these toxicities is unknown.

"Since carfilzomib produced an ORR of only 22% in the primary efficacy study, it may not provide an advantage over available therapy," the agency concluded. "FDA is very concerned with the severe toxicities, including deaths that are associated with the use of this agent. The pathogenesis of these toxicities is not understood. Considering these factors, the risks of carfilzomib may not outweigh its benefits."

The tone of the FDA’s briefing documents suggests that Onyx will have to make the case that the toxicities seen with carfilzomib can be managed.

Onyx’s briefing documents do not reflect any plans for a Risk Evaluation and Mitigation Strategy. The company said that carfilzomib was "generally well tolerated" in Study 3. "Although serious AEs were observed, the rates and types of these events were consistent with prior reported outcomes in this end-stage patient population, and treatment risk can be appropriately managed through patient selection, dose reduction algorithms, and other supportive measures."

Phase III Trials Underway

Onyx has taken a risk in pursuing approval based upon the results of a single-arm phase II trial. The existence of two ongoing phase III trials could help garner ODAC’s backing for accelerated approval by giving the committee confidence that further confirmatory data will be forthcoming within a given period of time. Alternatively, ODAC and the FDA could favor waiting on the confirmatory safety and efficacy evidence from these studies before allowing carfilzomib onto the market.

Onyx is currently conducting the ASPIRE study under a Special Protocol Assessment. The phase III, randomized trial is testing a combination of lenalidomide and dexamethasone, with or without carfilzomib, in 792 relapsed multiple myeloma patients who received one to three prior therapies. The primary end point is progression-free survival. The study is fully enrolled, and a final analysis is expected in mid-2014.

The ongoing FOCUS trial was designed pursuant to recommendations from the European Medicines Agency. The randomized trial is comparing carfilzomib to corticosteroids and optional low-dose cyclophosphamide in relapsed/refractory patients who have received three or more lines of therapy. The primary efficacy end point is overall survival. More than half of the targeted 302 patients had been enrolled as of March 2012; final analysis is projected for mid-2014.

Editor’s note: This story appears courtesy of "The Pink Sheet," a weekly Elsevier publication covering pharmaceutical business and policy issues. To learn more, contact customer care at 800-332-2181 or sign up for a free trial.

Serious cardiac, pulmonary, and hepatic toxicities associated with Onyx Pharmaceuticals Inc.’s investigational multiple myeloma drug Kyprolis (carfilzomib) may outweigh its benefits in a patient population that has not been shown to be refractory or intolerant to all available treatments, the Food and Drug Administration announced.

In briefing documents released ahead of the Oncologic Drugs Advisory Committee’s June 20 review of carfilzomib, the FDA said it is "very concerned" with the severe toxicities associated with the second-generation proteasome inhibitor and questions whether it is possible to identify patients at high risk for life-threatening, drug-related toxicities.

The agency also questions whether a lone, single-arm phase II trial provides sufficient evidence demonstrating that carfilzomib is beneficial over other available therapies in a relapsed/refractory population. Only a minority of all patients in the study were shown to be unresponsive or intolerant to most of the existing approved treatments for multiple myeloma.

The FDA seeks an ODAC vote on whether carfilzomib’s risk/benefit assessment is favorable for the indication requested. In considering this question, the committee will have to weigh whether accelerated approval is justified now, or whether an approval decision should await data from ongoing phase III trials that are expected to provide more clarity on the drug’s safety and efficacy profile in the relapsed/refractory setting.

Benefit Over Existing Therapies

Onyx is seeking carfilzomib’s approval for treatment of patients with relapsed and refractory multiple myeloma who have received at least two prior lines of therapy that included a proteasome inhibitor and an immunomodulatory agent. The NDA seeking accelerated approval was submitted in September 2011. The FDA denied Onyx’s request for priority review; the user fee goal date under a 10-month standard review is July 27.

The FDA’s briefing documents released on June 18 seek to put carfilzomib’s proposed use into the context of the seven drugs across five classes that are currently approved for treating multiple myeloma. Onyx is seeking approval based upon the results of Study PX-171-003 Part 2 (Study 3), a single-arm, phase II study of 266 patients. Subjects were required to have received prior treatment with bortezomib and either thalidomide or lenalidomide. They also must have received an alkylating agent, either alone or in combination with other multiple myeloma treatments, and an anthracycline, either alone or in combination with other treatments unless not clinically indicated.

The agency’s review notes that accelerated approval is a regulatory pathway for drugs that treat serious or life-threatening illnesses and that provide meaningful therapeutic benefit to patients over existing treatments. "Therefore, it is important to analyze the prior treatment history of each patient entered onto the primary efficacy phase II study (Study 3), and to determine whether each patient had been documented to be unresponsive to or intolerant of each of the drugs which have been approved by the FDA as therapy for multiple myeloma," the FDA said.

"Of the 266 patients enrolled in the study, 35.7% never received anthracyclines, 34.2% never received cyclophosphamide, 15.4% never received melphalan, and only 1.9% of patients were exposed to carmustine," the FDA said. Although 86.8% of patients were documented to be unresponsive or intolerant to both bortezomib and lenalidomide, only 56% were shown to be unresponsive or intolerant to thalidomide. Less than half were shown to be unresponsive or intolerant to anthracyclines (36.8%), cyclophosphamide (34.6%), or melphalan (28.9%).

The trial’s primary end point was overall response rate, as assessed by an independent review committee. The sponsor’s reported ORR was 22.9% in the intent-to-treat population. The FDA analyzed the results according to therapies for which patients were unresponsive or intolerant, and the ORR in these groups ranged from 20.2% to 23.2%.

The sponsor reported a median duration of response of 7.8 months; the FDA used a different definition to calculate duration of response and came up with a median of 6.5 months.

The agency suggested the efficacy results may have been confounded by concomitant use of the steroid dexamethasone in all subjects to reduce transfusion-related reactions. Dexamethasone is routinely given either alone or with other therapies to treat patients with multiple myeloma, the FDA pointed out. Although the dose given in Study 3 was lower than the amount typically given, "a therapeutic effect cannot be ruled out in a single-arm trial. In Study 3, the actual treatment effect of carfilzomib is confounded by the concomitant use of dexamethasone in the study and the response rates may be lower in the absence of steroids."

Deaths, SAEs, and Discontinuations

There were a total of 24 on-study deaths in the trial. Although disease progression accounted for half of these, as many as nine others were directly or possibly related to cardiac causes, the FDA said, and two deaths were blamed on hepatic failure.

Across the 526 multiple myeloma patients enrolled in phase II studies, 8% experienced a cardiac serious adverse event (SAE), and 7% experienced pulmonary toxicity. The majority of these serious adverse events were grade 3 or 4 toxicities. The most frequent cardiac SAEs were heart failure and cardiac arrest. Major adverse events leading to carfilzomib discontinuation across the phase II trials were dyspnea, pneumonia, and heart failure.

The FDA noted that determining whether adverse events are drug related can be problematic in the setting of single-arm trials.

"In general, the cause of adverse events from single-arm trials where the drug effect is unknown must be assigned to the experimental therapy," the FDA said. "Among the safety population of patients with multiple myeloma enrolled in phase II studies, there are several organ systems in which a higher incidence of adverse events has occurred than would be expected in this population of patients with multiple myeloma including cardiac, pulmonary, and hepatic toxicities, which must be assigned to carfilzomib. In addition to significant life-threatening adverse events associated with the heart, lung, and liver, a separate and distinct set of adverse events was associated with the infusion of carfilzomib."

Multiple myeloma patients treated with immunomodulatory agents do not show this pattern of cardiac, pulmonary, and hepatic toxicities, the FDA said. The agency also noted that cardiac and pulmonary toxicities, among others, were seen in preclinical studies of carfilzomib, although the pathogenesis of these toxicities is unknown.

"Since carfilzomib produced an ORR of only 22% in the primary efficacy study, it may not provide an advantage over available therapy," the agency concluded. "FDA is very concerned with the severe toxicities, including deaths that are associated with the use of this agent. The pathogenesis of these toxicities is not understood. Considering these factors, the risks of carfilzomib may not outweigh its benefits."

The tone of the FDA’s briefing documents suggests that Onyx will have to make the case that the toxicities seen with carfilzomib can be managed.

Onyx’s briefing documents do not reflect any plans for a Risk Evaluation and Mitigation Strategy. The company said that carfilzomib was "generally well tolerated" in Study 3. "Although serious AEs were observed, the rates and types of these events were consistent with prior reported outcomes in this end-stage patient population, and treatment risk can be appropriately managed through patient selection, dose reduction algorithms, and other supportive measures."

Phase III Trials Underway

Onyx has taken a risk in pursuing approval based upon the results of a single-arm phase II trial. The existence of two ongoing phase III trials could help garner ODAC’s backing for accelerated approval by giving the committee confidence that further confirmatory data will be forthcoming within a given period of time. Alternatively, ODAC and the FDA could favor waiting on the confirmatory safety and efficacy evidence from these studies before allowing carfilzomib onto the market.

Onyx is currently conducting the ASPIRE study under a Special Protocol Assessment. The phase III, randomized trial is testing a combination of lenalidomide and dexamethasone, with or without carfilzomib, in 792 relapsed multiple myeloma patients who received one to three prior therapies. The primary end point is progression-free survival. The study is fully enrolled, and a final analysis is expected in mid-2014.

The ongoing FOCUS trial was designed pursuant to recommendations from the European Medicines Agency. The randomized trial is comparing carfilzomib to corticosteroids and optional low-dose cyclophosphamide in relapsed/refractory patients who have received three or more lines of therapy. The primary efficacy end point is overall survival. More than half of the targeted 302 patients had been enrolled as of March 2012; final analysis is projected for mid-2014.

Editor’s note: This story appears courtesy of "The Pink Sheet," a weekly Elsevier publication covering pharmaceutical business and policy issues. To learn more, contact customer care at 800-332-2181 or sign up for a free trial.

Serious cardiac, pulmonary, and hepatic toxicities associated with Onyx Pharmaceuticals Inc.’s investigational multiple myeloma drug Kyprolis (carfilzomib) may outweigh its benefits in a patient population that has not been shown to be refractory or intolerant to all available treatments, the Food and Drug Administration announced.

In briefing documents released ahead of the Oncologic Drugs Advisory Committee’s June 20 review of carfilzomib, the FDA said it is "very concerned" with the severe toxicities associated with the second-generation proteasome inhibitor and questions whether it is possible to identify patients at high risk for life-threatening, drug-related toxicities.

The agency also questions whether a lone, single-arm phase II trial provides sufficient evidence demonstrating that carfilzomib is beneficial over other available therapies in a relapsed/refractory population. Only a minority of all patients in the study were shown to be unresponsive or intolerant to most of the existing approved treatments for multiple myeloma.

The FDA seeks an ODAC vote on whether carfilzomib’s risk/benefit assessment is favorable for the indication requested. In considering this question, the committee will have to weigh whether accelerated approval is justified now, or whether an approval decision should await data from ongoing phase III trials that are expected to provide more clarity on the drug’s safety and efficacy profile in the relapsed/refractory setting.

Benefit Over Existing Therapies

Onyx is seeking carfilzomib’s approval for treatment of patients with relapsed and refractory multiple myeloma who have received at least two prior lines of therapy that included a proteasome inhibitor and an immunomodulatory agent. The NDA seeking accelerated approval was submitted in September 2011. The FDA denied Onyx’s request for priority review; the user fee goal date under a 10-month standard review is July 27.

The FDA’s briefing documents released on June 18 seek to put carfilzomib’s proposed use into the context of the seven drugs across five classes that are currently approved for treating multiple myeloma. Onyx is seeking approval based upon the results of Study PX-171-003 Part 2 (Study 3), a single-arm, phase II study of 266 patients. Subjects were required to have received prior treatment with bortezomib and either thalidomide or lenalidomide. They also must have received an alkylating agent, either alone or in combination with other multiple myeloma treatments, and an anthracycline, either alone or in combination with other treatments unless not clinically indicated.

The agency’s review notes that accelerated approval is a regulatory pathway for drugs that treat serious or life-threatening illnesses and that provide meaningful therapeutic benefit to patients over existing treatments. "Therefore, it is important to analyze the prior treatment history of each patient entered onto the primary efficacy phase II study (Study 3), and to determine whether each patient had been documented to be unresponsive to or intolerant of each of the drugs which have been approved by the FDA as therapy for multiple myeloma," the FDA said.

"Of the 266 patients enrolled in the study, 35.7% never received anthracyclines, 34.2% never received cyclophosphamide, 15.4% never received melphalan, and only 1.9% of patients were exposed to carmustine," the FDA said. Although 86.8% of patients were documented to be unresponsive or intolerant to both bortezomib and lenalidomide, only 56% were shown to be unresponsive or intolerant to thalidomide. Less than half were shown to be unresponsive or intolerant to anthracyclines (36.8%), cyclophosphamide (34.6%), or melphalan (28.9%).

The trial’s primary end point was overall response rate, as assessed by an independent review committee. The sponsor’s reported ORR was 22.9% in the intent-to-treat population. The FDA analyzed the results according to therapies for which patients were unresponsive or intolerant, and the ORR in these groups ranged from 20.2% to 23.2%.

The sponsor reported a median duration of response of 7.8 months; the FDA used a different definition to calculate duration of response and came up with a median of 6.5 months.

The agency suggested the efficacy results may have been confounded by concomitant use of the steroid dexamethasone in all subjects to reduce transfusion-related reactions. Dexamethasone is routinely given either alone or with other therapies to treat patients with multiple myeloma, the FDA pointed out. Although the dose given in Study 3 was lower than the amount typically given, "a therapeutic effect cannot be ruled out in a single-arm trial. In Study 3, the actual treatment effect of carfilzomib is confounded by the concomitant use of dexamethasone in the study and the response rates may be lower in the absence of steroids."

Deaths, SAEs, and Discontinuations

There were a total of 24 on-study deaths in the trial. Although disease progression accounted for half of these, as many as nine others were directly or possibly related to cardiac causes, the FDA said, and two deaths were blamed on hepatic failure.

Across the 526 multiple myeloma patients enrolled in phase II studies, 8% experienced a cardiac serious adverse event (SAE), and 7% experienced pulmonary toxicity. The majority of these serious adverse events were grade 3 or 4 toxicities. The most frequent cardiac SAEs were heart failure and cardiac arrest. Major adverse events leading to carfilzomib discontinuation across the phase II trials were dyspnea, pneumonia, and heart failure.

The FDA noted that determining whether adverse events are drug related can be problematic in the setting of single-arm trials.

"In general, the cause of adverse events from single-arm trials where the drug effect is unknown must be assigned to the experimental therapy," the FDA said. "Among the safety population of patients with multiple myeloma enrolled in phase II studies, there are several organ systems in which a higher incidence of adverse events has occurred than would be expected in this population of patients with multiple myeloma including cardiac, pulmonary, and hepatic toxicities, which must be assigned to carfilzomib. In addition to significant life-threatening adverse events associated with the heart, lung, and liver, a separate and distinct set of adverse events was associated with the infusion of carfilzomib."

Multiple myeloma patients treated with immunomodulatory agents do not show this pattern of cardiac, pulmonary, and hepatic toxicities, the FDA said. The agency also noted that cardiac and pulmonary toxicities, among others, were seen in preclinical studies of carfilzomib, although the pathogenesis of these toxicities is unknown.

"Since carfilzomib produced an ORR of only 22% in the primary efficacy study, it may not provide an advantage over available therapy," the agency concluded. "FDA is very concerned with the severe toxicities, including deaths that are associated with the use of this agent. The pathogenesis of these toxicities is not understood. Considering these factors, the risks of carfilzomib may not outweigh its benefits."

The tone of the FDA’s briefing documents suggests that Onyx will have to make the case that the toxicities seen with carfilzomib can be managed.

Onyx’s briefing documents do not reflect any plans for a Risk Evaluation and Mitigation Strategy. The company said that carfilzomib was "generally well tolerated" in Study 3. "Although serious AEs were observed, the rates and types of these events were consistent with prior reported outcomes in this end-stage patient population, and treatment risk can be appropriately managed through patient selection, dose reduction algorithms, and other supportive measures."

Phase III Trials Underway

Onyx has taken a risk in pursuing approval based upon the results of a single-arm phase II trial. The existence of two ongoing phase III trials could help garner ODAC’s backing for accelerated approval by giving the committee confidence that further confirmatory data will be forthcoming within a given period of time. Alternatively, ODAC and the FDA could favor waiting on the confirmatory safety and efficacy evidence from these studies before allowing carfilzomib onto the market.

Onyx is currently conducting the ASPIRE study under a Special Protocol Assessment. The phase III, randomized trial is testing a combination of lenalidomide and dexamethasone, with or without carfilzomib, in 792 relapsed multiple myeloma patients who received one to three prior therapies. The primary end point is progression-free survival. The study is fully enrolled, and a final analysis is expected in mid-2014.

The ongoing FOCUS trial was designed pursuant to recommendations from the European Medicines Agency. The randomized trial is comparing carfilzomib to corticosteroids and optional low-dose cyclophosphamide in relapsed/refractory patients who have received three or more lines of therapy. The primary efficacy end point is overall survival. More than half of the targeted 302 patients had been enrolled as of March 2012; final analysis is projected for mid-2014.

Editor’s note: This story appears courtesy of "The Pink Sheet," a weekly Elsevier publication covering pharmaceutical business and policy issues. To learn more, contact customer care at 800-332-2181 or sign up for a free trial.

AMSTERDAM – Crizotinib has shown significant antitumor activity in adult patients with lymphomas that express the anaplastic lymphoma kinase gene and who were resistant to the effects of at least three lines of previous therapy.

During a compassionate use program, eight of nine patients with anaplastic lymphoma kinase (ALK)–positive lymphoma responded to crizotinib (Xalkori). Six patients had complete responses, and four achieved durable responses lasting more than 6 months.

Sara Freeman/IMNG Medical Media

These data mirror positive early results already seen in pediatric anaplastic large cell lymphoma (ALCL). Seven of eight children treated with crizotinib had complete and durable responses, investigators reported at the American Society of Clinical Oncology annual meeting.

"Clinically, ALK+ lymphomas are known for their aggressiveness," said Dr. Carlo Gambacorti-Passerini, who presented the adult findings June 17 at the annual congress of the European Hematology Association. These data give a strong signal that further investigation in ALK-positive lymphomas is warranted.

Crizotinib was approved by the Food and Drug Administration for the treatment of ALK-driven non–small cell lung cancer (NSCLC) last August, but these new data suggest that responses may be even better in these lymphoma patients.

"It looks like, compared to EMF4-ALK-positive non–small cell lung cancer, the responses are much more durable," observed Dr. Matthias Theobald of Medizinische Klinik und Poliklink in Mainz, Germany, who chaired the session in which the adult findings were presented.

"Why lung cancer patients only have a median duration of responses of 10-12 months is not very clear," responded Dr. Carlo Gambacorti-Passerini, professor of internal medicine at the University of Milan–Bicocca and director of the clinical research unit at S. Gerardo Hospital, both in Monza, Italy.

It is also not apparent why some patients with ALK-positive lymphoma initially benefit while others develop resistance with time. "The main issue here is that [nearly] everybody responds, but after 2-3 months we see a divide," Dr. Gambacorti-Passerini said.

Four men and five women aged between 20 and 56 years (median age, 31 years) received crizotinib at a dose of 250 mg twice daily as part of a compassionate protocol. Seven patients had ALCL, and two patients had diffuse large cell lymphoma according to WHO criteria.

The median number of previous lines of therapy they had collectively received was three, although some had received up to five prior chemotherapy regimens, three had undergone autologous bone marrow transplant, and one patient an allogenic bone marrow transplant. While on crizotinib, steroid use or the use of drugs with antineoplastic activity was not allowed.

The effects of crizotinib were carefully assessed via physical exam, examination of bone marrow aspirate, positron-emission tomography and computed tomography scans, and blood tests before treatment initiation and at monthly intervals for the first 3 months, then every 3 months for up to 2 years. Disease status was also evaluated according to standard RECIST criteria.

After a median follow-up of 8 months, six patients had achieved a complete response to crizotinib, lasting for 2, 5, 8, 13, 18, or 24 months or more, respectively. A further two patients had a partial response.

Dr. Gambacorti-Passerini reported responses to treatment were "very rapid," with alleviation of fever within 2-10 days and time to normalization of serum lactate dehydrogenase within a month.

Furthermore, three patients were still on treatment with crizotinib. Six patients had discontinued: one because of patient request and five because of disease progression. The patient who discontinued by request did so because of severe gastroparesis unrelated to crizotinib and after a planned stoppage of the drug for a stem cell transplant.

Importantly, overall survival at 24 months appears to be just over 40%.

The most common side effects and lab abnormalities were ocular flashes, which all nine patients experienced, but these were of grade 1 or 2 and usually a temporary effect; one patient each had a grade 1-2 peripheral edema, a grade 3 neutropenia, and a grade 2 liver function test abnormality.

"These data show that crizotinib was well tolerated in this population of heavily pretreated patients," Dr. Gambacorti-Passerini concluded. He noted that patients have been treated with crizotinib for 2 years or more, which is the longest anyone has received the drug.

"Now, crizotinib is being evaluated in a registration study, which will start after this compassionate use," he added. This international phase I study (NCT01121588) is currently enrolling patients, and there are also suggestions of using crizotinib as first-line treatment or in combination with other agents for ALK+ lymphomas.

Dr. Gambacorti-Passerini has received research funding from Pfizer, which supported the compassionate use program.

AMSTERDAM – Crizotinib has shown significant antitumor activity in adult patients with lymphomas that express the anaplastic lymphoma kinase gene and who were resistant to the effects of at least three lines of previous therapy.

During a compassionate use program, eight of nine patients with anaplastic lymphoma kinase (ALK)–positive lymphoma responded to crizotinib (Xalkori). Six patients had complete responses, and four achieved durable responses lasting more than 6 months.

Sara Freeman/IMNG Medical Media

These data mirror positive early results already seen in pediatric anaplastic large cell lymphoma (ALCL). Seven of eight children treated with crizotinib had complete and durable responses, investigators reported at the American Society of Clinical Oncology annual meeting.

"Clinically, ALK+ lymphomas are known for their aggressiveness," said Dr. Carlo Gambacorti-Passerini, who presented the adult findings June 17 at the annual congress of the European Hematology Association. These data give a strong signal that further investigation in ALK-positive lymphomas is warranted.

Crizotinib was approved by the Food and Drug Administration for the treatment of ALK-driven non–small cell lung cancer (NSCLC) last August, but these new data suggest that responses may be even better in these lymphoma patients.

"It looks like, compared to EMF4-ALK-positive non–small cell lung cancer, the responses are much more durable," observed Dr. Matthias Theobald of Medizinische Klinik und Poliklink in Mainz, Germany, who chaired the session in which the adult findings were presented.

"Why lung cancer patients only have a median duration of responses of 10-12 months is not very clear," responded Dr. Carlo Gambacorti-Passerini, professor of internal medicine at the University of Milan–Bicocca and director of the clinical research unit at S. Gerardo Hospital, both in Monza, Italy.

It is also not apparent why some patients with ALK-positive lymphoma initially benefit while others develop resistance with time. "The main issue here is that [nearly] everybody responds, but after 2-3 months we see a divide," Dr. Gambacorti-Passerini said.

Four men and five women aged between 20 and 56 years (median age, 31 years) received crizotinib at a dose of 250 mg twice daily as part of a compassionate protocol. Seven patients had ALCL, and two patients had diffuse large cell lymphoma according to WHO criteria.

The median number of previous lines of therapy they had collectively received was three, although some had received up to five prior chemotherapy regimens, three had undergone autologous bone marrow transplant, and one patient an allogenic bone marrow transplant. While on crizotinib, steroid use or the use of drugs with antineoplastic activity was not allowed.

The effects of crizotinib were carefully assessed via physical exam, examination of bone marrow aspirate, positron-emission tomography and computed tomography scans, and blood tests before treatment initiation and at monthly intervals for the first 3 months, then every 3 months for up to 2 years. Disease status was also evaluated according to standard RECIST criteria.

After a median follow-up of 8 months, six patients had achieved a complete response to crizotinib, lasting for 2, 5, 8, 13, 18, or 24 months or more, respectively. A further two patients had a partial response.

Dr. Gambacorti-Passerini reported responses to treatment were "very rapid," with alleviation of fever within 2-10 days and time to normalization of serum lactate dehydrogenase within a month.

Furthermore, three patients were still on treatment with crizotinib. Six patients had discontinued: one because of patient request and five because of disease progression. The patient who discontinued by request did so because of severe gastroparesis unrelated to crizotinib and after a planned stoppage of the drug for a stem cell transplant.

Importantly, overall survival at 24 months appears to be just over 40%.

The most common side effects and lab abnormalities were ocular flashes, which all nine patients experienced, but these were of grade 1 or 2 and usually a temporary effect; one patient each had a grade 1-2 peripheral edema, a grade 3 neutropenia, and a grade 2 liver function test abnormality.

"These data show that crizotinib was well tolerated in this population of heavily pretreated patients," Dr. Gambacorti-Passerini concluded. He noted that patients have been treated with crizotinib for 2 years or more, which is the longest anyone has received the drug.

"Now, crizotinib is being evaluated in a registration study, which will start after this compassionate use," he added. This international phase I study (NCT01121588) is currently enrolling patients, and there are also suggestions of using crizotinib as first-line treatment or in combination with other agents for ALK+ lymphomas.

Dr. Gambacorti-Passerini has received research funding from Pfizer, which supported the compassionate use program.

AMSTERDAM – Crizotinib has shown significant antitumor activity in adult patients with lymphomas that express the anaplastic lymphoma kinase gene and who were resistant to the effects of at least three lines of previous therapy.

During a compassionate use program, eight of nine patients with anaplastic lymphoma kinase (ALK)–positive lymphoma responded to crizotinib (Xalkori). Six patients had complete responses, and four achieved durable responses lasting more than 6 months.

Sara Freeman/IMNG Medical Media

These data mirror positive early results already seen in pediatric anaplastic large cell lymphoma (ALCL). Seven of eight children treated with crizotinib had complete and durable responses, investigators reported at the American Society of Clinical Oncology annual meeting.

"Clinically, ALK+ lymphomas are known for their aggressiveness," said Dr. Carlo Gambacorti-Passerini, who presented the adult findings June 17 at the annual congress of the European Hematology Association. These data give a strong signal that further investigation in ALK-positive lymphomas is warranted.

Crizotinib was approved by the Food and Drug Administration for the treatment of ALK-driven non–small cell lung cancer (NSCLC) last August, but these new data suggest that responses may be even better in these lymphoma patients.

"It looks like, compared to EMF4-ALK-positive non–small cell lung cancer, the responses are much more durable," observed Dr. Matthias Theobald of Medizinische Klinik und Poliklink in Mainz, Germany, who chaired the session in which the adult findings were presented.

"Why lung cancer patients only have a median duration of responses of 10-12 months is not very clear," responded Dr. Carlo Gambacorti-Passerini, professor of internal medicine at the University of Milan–Bicocca and director of the clinical research unit at S. Gerardo Hospital, both in Monza, Italy.

It is also not apparent why some patients with ALK-positive lymphoma initially benefit while others develop resistance with time. "The main issue here is that [nearly] everybody responds, but after 2-3 months we see a divide," Dr. Gambacorti-Passerini said.

Four men and five women aged between 20 and 56 years (median age, 31 years) received crizotinib at a dose of 250 mg twice daily as part of a compassionate protocol. Seven patients had ALCL, and two patients had diffuse large cell lymphoma according to WHO criteria.

The median number of previous lines of therapy they had collectively received was three, although some had received up to five prior chemotherapy regimens, three had undergone autologous bone marrow transplant, and one patient an allogenic bone marrow transplant. While on crizotinib, steroid use or the use of drugs with antineoplastic activity was not allowed.

The effects of crizotinib were carefully assessed via physical exam, examination of bone marrow aspirate, positron-emission tomography and computed tomography scans, and blood tests before treatment initiation and at monthly intervals for the first 3 months, then every 3 months for up to 2 years. Disease status was also evaluated according to standard RECIST criteria.

After a median follow-up of 8 months, six patients had achieved a complete response to crizotinib, lasting for 2, 5, 8, 13, 18, or 24 months or more, respectively. A further two patients had a partial response.

Dr. Gambacorti-Passerini reported responses to treatment were "very rapid," with alleviation of fever within 2-10 days and time to normalization of serum lactate dehydrogenase within a month.

Furthermore, three patients were still on treatment with crizotinib. Six patients had discontinued: one because of patient request and five because of disease progression. The patient who discontinued by request did so because of severe gastroparesis unrelated to crizotinib and after a planned stoppage of the drug for a stem cell transplant.

Importantly, overall survival at 24 months appears to be just over 40%.

The most common side effects and lab abnormalities were ocular flashes, which all nine patients experienced, but these were of grade 1 or 2 and usually a temporary effect; one patient each had a grade 1-2 peripheral edema, a grade 3 neutropenia, and a grade 2 liver function test abnormality.

"These data show that crizotinib was well tolerated in this population of heavily pretreated patients," Dr. Gambacorti-Passerini concluded. He noted that patients have been treated with crizotinib for 2 years or more, which is the longest anyone has received the drug.

"Now, crizotinib is being evaluated in a registration study, which will start after this compassionate use," he added. This international phase I study (NCT01121588) is currently enrolling patients, and there are also suggestions of using crizotinib as first-line treatment or in combination with other agents for ALK+ lymphomas.

Dr. Gambacorti-Passerini has received research funding from Pfizer, which supported the compassionate use program.

CHICAGO – Breast cancer risk is much higher than previously recognized among women who received chest radiation for Hodgkin’s lymphoma when they were children, investigators reported.

By the time these survivors are 50 years of age, breast cancer incidence is 30% – "remarkably similar" to the 31% incidence observed in the high-risk group of women with BRCA1 mutations, Chaya S. Moskowitz, Ph.D., and her colleagues determined in a study presented at the annual meeting of the American Society of Clinical Oncology.

Although the effect was less dramatic, cumulative risk also was elevated in survivors of other childhood cancers treated with chest radiation, reaching 24% overall by age 50, Dr. Moskowitz said at a press briefing. Among the general population of women in the United States, it is 4% at that benchmark, she noted.

Particularly concerning is the heightened risk observed in women who received less radiation than the current threshold at which the Children’s Oncology Group (COG) recommends breast cancer surveillance. The COG says that survivors who received 20 Gy or more of chest radiation should start annual mammograms at age 25 years or 8 years after radiotherapy, whichever comes later.

In this group, 12% of survivors will develop breast cancer by age 40, said Dr. Moskowitz, a biostatistician at Memorial Sloan-Kettering Cancer Center in New York. The study showed that breast cancer incidence also was elevated, albeit not as dramatically – 7% by age 40 – among survivors who received 10-19 Gy of radiation.

Excess risk in those treated with 10-19 Gy warrants "consideration of breast cancer surveillance strategies similar to the current recommendations for women treated with [more than] 20 Gy," the investigators concluded.

About 50,000 survivors received 20 Gy or more of radiation and, therefore, meet the current threshold, Dr. Moskowitz said. Lowering the threshold to include survivors who were treated with 10-19 Gy of chest radiation would add another 7,000-9,000 women.

Increasing public awareness is crucial to increasing surveillance. "Many women who were treated with chest radiation don’t know they have an increased risk of breast cancer," she said. "Their physicians may or may not know, but many physicians are not aware of the guidelines."

Moreover, many survivors don’t know their radiation exposure, and she urged them to try to find those records from long, long ago.

The analysis – a report from the Childhood Cancer Survivor Study (CCSS) and the Women’s Environmental Cancer and Radiation Epidemiology (WECARE) study – mined data on 1,268 women survivors of childhood cancers diagnosed from 1970 to 1986 and on 4,570 first-degree relatives of women who had survived at least 1 year after being diagnosed with breast cancer.

Median follow-up was 26 years in the childhood survivors, of whom 175 women were diagnosed with breast cancer as adults. Median latency was 23 years after treatment, and diagnosis was made at a median age of 38 years.

Multiple studies have shown an increased risk of breast cancer in women who received chest radiation as children, Dr. Moskowitz said. This large study has substantially longer follow-up and was surprising in the magnitude of risk it documents.

Chest radiation doses are lower today, and mantle field radiation – which had been used almost exclusively in Hodgkin’s lymphoma – is no longer used, but other regimens are still in the clinic, she added.

Another surprise from the study was that whole lung radiation, even at low doses, can heighten breast cancer risk. "Women treated with whole lung radiation have a risk of breast cancer that is higher than previous recognized and may benefit from surveillance strategies," she said.

"These are striking data and certainly warrant our careful attention," commented press briefing chair Dr. Nicholas Vogelzang, chair and medical director of the developmental therapeutics committee at the Comprehensive Cancer Centers of Nevada, Las Vegas, and cochair of the genitourinary committee for U.S. Oncology Research.

"The benefit of curing a cancer is you can live 25 or more years," he said, noting that curves for breast cancer incidence rose after 25 years in a graphic representation of the data presented. "We have an obligation to those many thousands of young women whom we treated many years ago."

The investigators said that they had no relevant financial disclosures.

CHICAGO – Breast cancer risk is much higher than previously recognized among women who received chest radiation for Hodgkin’s lymphoma when they were children, investigators reported.

By the time these survivors are 50 years of age, breast cancer incidence is 30% – "remarkably similar" to the 31% incidence observed in the high-risk group of women with BRCA1 mutations, Chaya S. Moskowitz, Ph.D., and her colleagues determined in a study presented at the annual meeting of the American Society of Clinical Oncology.

Although the effect was less dramatic, cumulative risk also was elevated in survivors of other childhood cancers treated with chest radiation, reaching 24% overall by age 50, Dr. Moskowitz said at a press briefing. Among the general population of women in the United States, it is 4% at that benchmark, she noted.

Particularly concerning is the heightened risk observed in women who received less radiation than the current threshold at which the Children’s Oncology Group (COG) recommends breast cancer surveillance. The COG says that survivors who received 20 Gy or more of chest radiation should start annual mammograms at age 25 years or 8 years after radiotherapy, whichever comes later.

In this group, 12% of survivors will develop breast cancer by age 40, said Dr. Moskowitz, a biostatistician at Memorial Sloan-Kettering Cancer Center in New York. The study showed that breast cancer incidence also was elevated, albeit not as dramatically – 7% by age 40 – among survivors who received 10-19 Gy of radiation.

Excess risk in those treated with 10-19 Gy warrants "consideration of breast cancer surveillance strategies similar to the current recommendations for women treated with [more than] 20 Gy," the investigators concluded.

About 50,000 survivors received 20 Gy or more of radiation and, therefore, meet the current threshold, Dr. Moskowitz said. Lowering the threshold to include survivors who were treated with 10-19 Gy of chest radiation would add another 7,000-9,000 women.

Increasing public awareness is crucial to increasing surveillance. "Many women who were treated with chest radiation don’t know they have an increased risk of breast cancer," she said. "Their physicians may or may not know, but many physicians are not aware of the guidelines."

Moreover, many survivors don’t know their radiation exposure, and she urged them to try to find those records from long, long ago.

The analysis – a report from the Childhood Cancer Survivor Study (CCSS) and the Women’s Environmental Cancer and Radiation Epidemiology (WECARE) study – mined data on 1,268 women survivors of childhood cancers diagnosed from 1970 to 1986 and on 4,570 first-degree relatives of women who had survived at least 1 year after being diagnosed with breast cancer.

Median follow-up was 26 years in the childhood survivors, of whom 175 women were diagnosed with breast cancer as adults. Median latency was 23 years after treatment, and diagnosis was made at a median age of 38 years.

Multiple studies have shown an increased risk of breast cancer in women who received chest radiation as children, Dr. Moskowitz said. This large study has substantially longer follow-up and was surprising in the magnitude of risk it documents.

Chest radiation doses are lower today, and mantle field radiation – which had been used almost exclusively in Hodgkin’s lymphoma – is no longer used, but other regimens are still in the clinic, she added.

Another surprise from the study was that whole lung radiation, even at low doses, can heighten breast cancer risk. "Women treated with whole lung radiation have a risk of breast cancer that is higher than previous recognized and may benefit from surveillance strategies," she said.

"These are striking data and certainly warrant our careful attention," commented press briefing chair Dr. Nicholas Vogelzang, chair and medical director of the developmental therapeutics committee at the Comprehensive Cancer Centers of Nevada, Las Vegas, and cochair of the genitourinary committee for U.S. Oncology Research.

"The benefit of curing a cancer is you can live 25 or more years," he said, noting that curves for breast cancer incidence rose after 25 years in a graphic representation of the data presented. "We have an obligation to those many thousands of young women whom we treated many years ago."

The investigators said that they had no relevant financial disclosures.

CHICAGO – Breast cancer risk is much higher than previously recognized among women who received chest radiation for Hodgkin’s lymphoma when they were children, investigators reported.

By the time these survivors are 50 years of age, breast cancer incidence is 30% – "remarkably similar" to the 31% incidence observed in the high-risk group of women with BRCA1 mutations, Chaya S. Moskowitz, Ph.D., and her colleagues determined in a study presented at the annual meeting of the American Society of Clinical Oncology.

Although the effect was less dramatic, cumulative risk also was elevated in survivors of other childhood cancers treated with chest radiation, reaching 24% overall by age 50, Dr. Moskowitz said at a press briefing. Among the general population of women in the United States, it is 4% at that benchmark, she noted.

Particularly concerning is the heightened risk observed in women who received less radiation than the current threshold at which the Children’s Oncology Group (COG) recommends breast cancer surveillance. The COG says that survivors who received 20 Gy or more of chest radiation should start annual mammograms at age 25 years or 8 years after radiotherapy, whichever comes later.

In this group, 12% of survivors will develop breast cancer by age 40, said Dr. Moskowitz, a biostatistician at Memorial Sloan-Kettering Cancer Center in New York. The study showed that breast cancer incidence also was elevated, albeit not as dramatically – 7% by age 40 – among survivors who received 10-19 Gy of radiation.

Excess risk in those treated with 10-19 Gy warrants "consideration of breast cancer surveillance strategies similar to the current recommendations for women treated with [more than] 20 Gy," the investigators concluded.

About 50,000 survivors received 20 Gy or more of radiation and, therefore, meet the current threshold, Dr. Moskowitz said. Lowering the threshold to include survivors who were treated with 10-19 Gy of chest radiation would add another 7,000-9,000 women.

Increasing public awareness is crucial to increasing surveillance. "Many women who were treated with chest radiation don’t know they have an increased risk of breast cancer," she said. "Their physicians may or may not know, but many physicians are not aware of the guidelines."

Moreover, many survivors don’t know their radiation exposure, and she urged them to try to find those records from long, long ago.

The analysis – a report from the Childhood Cancer Survivor Study (CCSS) and the Women’s Environmental Cancer and Radiation Epidemiology (WECARE) study – mined data on 1,268 women survivors of childhood cancers diagnosed from 1970 to 1986 and on 4,570 first-degree relatives of women who had survived at least 1 year after being diagnosed with breast cancer.

Median follow-up was 26 years in the childhood survivors, of whom 175 women were diagnosed with breast cancer as adults. Median latency was 23 years after treatment, and diagnosis was made at a median age of 38 years.

Multiple studies have shown an increased risk of breast cancer in women who received chest radiation as children, Dr. Moskowitz said. This large study has substantially longer follow-up and was surprising in the magnitude of risk it documents.

Chest radiation doses are lower today, and mantle field radiation – which had been used almost exclusively in Hodgkin’s lymphoma – is no longer used, but other regimens are still in the clinic, she added.

Another surprise from the study was that whole lung radiation, even at low doses, can heighten breast cancer risk. "Women treated with whole lung radiation have a risk of breast cancer that is higher than previous recognized and may benefit from surveillance strategies," she said.

"These are striking data and certainly warrant our careful attention," commented press briefing chair Dr. Nicholas Vogelzang, chair and medical director of the developmental therapeutics committee at the Comprehensive Cancer Centers of Nevada, Las Vegas, and cochair of the genitourinary committee for U.S. Oncology Research.

"The benefit of curing a cancer is you can live 25 or more years," he said, noting that curves for breast cancer incidence rose after 25 years in a graphic representation of the data presented. "We have an obligation to those many thousands of young women whom we treated many years ago."

The investigators said that they had no relevant financial disclosures.

CHICAGO – Bendamustine-rituximab continues to outshine CHOP-rituximab for indolent and mantle cell lymphomas, based on the updated results of the StiL NHL1 study.

With a twofold higher rate of progression-free survival and several-fold reductions in the rates of associated toxicities, "bendamustine-rituximab could be considered the preferred first-line treatment for patients with these disease entities," Dr. Mathias J. Rummel said during a press conference at the annual meeting of the American Society of Clinical Oncology.

Bendamustine is marketed in the United States as Treanda (Cephalon). Bendamustine was developed 50 years ago in East Germany, Dr. Rummel said. Only after the reunification of Germany did physicians in the West learn about the drug and begin to conduct clinical trials and to publish the results.

A large randomized trial of 514 evaluable patients treated in community and hospital-based oncology groups in Germany, StiL NHL1 compared progression-free survival for the two regimens in patients with follicular, Waldenstrom’s, marginal zone, small lymphocytic, or mantle cell lymphomas.

Patients in the bendamustine-rituximab group had a median of 69.5 months of progression-free survival compared with 31.2 months with CHOP-rituximab. The benefit with bendamustine-rituximab was maintained in all histological subtypes except marginal zone lymphoma.

In patients with normal levels of lactic dehydrogenase (62%), progression-free survival was significantly prolonged with bendamustine-rituximab compared with CHOP-rituximab (P less than .001). In those with elevated levels of LDH (38%), progression-free survival was numerically, but not significantly, increased with bendamustine-rituximab (P = .118).

In patients with follicular lymphoma, follicular lymphoma international prognostic index (FLIPI) subgroups defined by 0-2 factors (favorable) and 3-5 factors (unfavorable) had longer progression-free survival with bendamustine-rituximab than with CHOP-rituximab. The longer progression-free survival was significant for both the favorable (P = .043) and unfavorable (P = .068) FLIPI subgroups.

Patients in the study were randomized for a maximum of six cycles to either bendamustine (90 mg/m² on day 1 and 2) and rituximab (375 mg/m² on day 1) or to CHOP-rituximab (cyclophosphamide 750 mg/m² on day 1, doxorubicin 50 mg/m² on day 1, vincristine 1.4 mg/m² on day 1, and prednisone 100 mg on days 1-5), and rituximab (375 mg/m² on day 1), according to Dr. Rummel of the University Hospital Giessen (Germany).

In the bendamustine-rituximab group, 74 salvage treatments had been initiated. In the CHOP-rituximab group, 116 salvage treatments were initiated. Of those in the CHOP-rituximab group, 52 patients received bendamustine-rituximab as a salvage regimen. Overall survival did not differ between the treatment arms, with 43 and 45 deaths in the two groups, respectively. Secondary malignancies were observed in 20 patients in the bendamustine-rituximab group compared with 23 in the CHOP-rituximab group, with 1 hematologic malignancy in each group (1 case of myelodysplastic syndrome in the bendamustine-rituximab group and 1 case of acute myelogenous leukemia in the CHOP-rituximab group).

Grade 3/4 hematotoxicities were significantly lower in the 261 patients in the bendamustine-rituximab group than in the 253 in the CHOP-rituximab group (P less than .0001). The percentage of cycles associated with leukopenia was 12% for bendamustine-rituximab patients and 38% for CHOP-rituximab patients. The percentage of cycles associated with neutropenia was nearly 11% with bendamustine-rituximab and more than 46% with CHOP-rituximab. The percentage of cycles that necessitated administration of granulocyte colony-stimulating factor (G-CSF) was 4% with bendamustine-rituximab and 20% with CHOP-rituximab. The rates of anemia and thrombocytopenia were comparable and low (less than 2% of cycles) for both regimens.

Importantly, alopecia did not occur with bendamustine-rituximab but was nearly universal with CHOP-rituximab, Dr. Rummel said. Paresthesias were noted in 18 of 261 bendamustine-rituximab patients and 73 of 253 CHOP-rituximab patients; stomatitis was seen in 16 and 73 patients, respectively. Both differences were significant (P less than .0001).

Conversely, the bendamustine-treated patients had more erythema (42 of 261 bendamustine-rituximab patients vs. 23 of 253 CHOP-rituximab patients) and allergic reactions (40 vs. 15, respectively). These were not dose-limiting toxicities. Infectious complications were frequent, and affected 96 bendamustine and 127 CHOP patients.

Next steps include a new trial called MAINTAIN that will examine rituximab maintenance therapy in 591 patients treated with bendamustine and rituximab. Patients will receive 2 years of rituximab maintenance therapy and will then be randomized to either observation or 2 more years of rituximab.

Dr. Rummel receives honoraria and research funding from Mundipharma and Roche.

CHICAGO – Bendamustine-rituximab continues to outshine CHOP-rituximab for indolent and mantle cell lymphomas, based on the updated results of the StiL NHL1 study.

With a twofold higher rate of progression-free survival and several-fold reductions in the rates of associated toxicities, "bendamustine-rituximab could be considered the preferred first-line treatment for patients with these disease entities," Dr. Mathias J. Rummel said during a press conference at the annual meeting of the American Society of Clinical Oncology.

Bendamustine is marketed in the United States as Treanda (Cephalon). Bendamustine was developed 50 years ago in East Germany, Dr. Rummel said. Only after the reunification of Germany did physicians in the West learn about the drug and begin to conduct clinical trials and to publish the results.

A large randomized trial of 514 evaluable patients treated in community and hospital-based oncology groups in Germany, StiL NHL1 compared progression-free survival for the two regimens in patients with follicular, Waldenstrom’s, marginal zone, small lymphocytic, or mantle cell lymphomas.

Patients in the bendamustine-rituximab group had a median of 69.5 months of progression-free survival compared with 31.2 months with CHOP-rituximab. The benefit with bendamustine-rituximab was maintained in all histological subtypes except marginal zone lymphoma.

In patients with normal levels of lactic dehydrogenase (62%), progression-free survival was significantly prolonged with bendamustine-rituximab compared with CHOP-rituximab (P less than .001). In those with elevated levels of LDH (38%), progression-free survival was numerically, but not significantly, increased with bendamustine-rituximab (P = .118).

In patients with follicular lymphoma, follicular lymphoma international prognostic index (FLIPI) subgroups defined by 0-2 factors (favorable) and 3-5 factors (unfavorable) had longer progression-free survival with bendamustine-rituximab than with CHOP-rituximab. The longer progression-free survival was significant for both the favorable (P = .043) and unfavorable (P = .068) FLIPI subgroups.

Patients in the study were randomized for a maximum of six cycles to either bendamustine (90 mg/m² on day 1 and 2) and rituximab (375 mg/m² on day 1) or to CHOP-rituximab (cyclophosphamide 750 mg/m² on day 1, doxorubicin 50 mg/m² on day 1, vincristine 1.4 mg/m² on day 1, and prednisone 100 mg on days 1-5), and rituximab (375 mg/m² on day 1), according to Dr. Rummel of the University Hospital Giessen (Germany).

In the bendamustine-rituximab group, 74 salvage treatments had been initiated. In the CHOP-rituximab group, 116 salvage treatments were initiated. Of those in the CHOP-rituximab group, 52 patients received bendamustine-rituximab as a salvage regimen. Overall survival did not differ between the treatment arms, with 43 and 45 deaths in the two groups, respectively. Secondary malignancies were observed in 20 patients in the bendamustine-rituximab group compared with 23 in the CHOP-rituximab group, with 1 hematologic malignancy in each group (1 case of myelodysplastic syndrome in the bendamustine-rituximab group and 1 case of acute myelogenous leukemia in the CHOP-rituximab group).

Grade 3/4 hematotoxicities were significantly lower in the 261 patients in the bendamustine-rituximab group than in the 253 in the CHOP-rituximab group (P less than .0001). The percentage of cycles associated with leukopenia was 12% for bendamustine-rituximab patients and 38% for CHOP-rituximab patients. The percentage of cycles associated with neutropenia was nearly 11% with bendamustine-rituximab and more than 46% with CHOP-rituximab. The percentage of cycles that necessitated administration of granulocyte colony-stimulating factor (G-CSF) was 4% with bendamustine-rituximab and 20% with CHOP-rituximab. The rates of anemia and thrombocytopenia were comparable and low (less than 2% of cycles) for both regimens.

Importantly, alopecia did not occur with bendamustine-rituximab but was nearly universal with CHOP-rituximab, Dr. Rummel said. Paresthesias were noted in 18 of 261 bendamustine-rituximab patients and 73 of 253 CHOP-rituximab patients; stomatitis was seen in 16 and 73 patients, respectively. Both differences were significant (P less than .0001).

Conversely, the bendamustine-treated patients had more erythema (42 of 261 bendamustine-rituximab patients vs. 23 of 253 CHOP-rituximab patients) and allergic reactions (40 vs. 15, respectively). These were not dose-limiting toxicities. Infectious complications were frequent, and affected 96 bendamustine and 127 CHOP patients.

Next steps include a new trial called MAINTAIN that will examine rituximab maintenance therapy in 591 patients treated with bendamustine and rituximab. Patients will receive 2 years of rituximab maintenance therapy and will then be randomized to either observation or 2 more years of rituximab.

Dr. Rummel receives honoraria and research funding from Mundipharma and Roche.

CHICAGO – Bendamustine-rituximab continues to outshine CHOP-rituximab for indolent and mantle cell lymphomas, based on the updated results of the StiL NHL1 study.

With a twofold higher rate of progression-free survival and several-fold reductions in the rates of associated toxicities, "bendamustine-rituximab could be considered the preferred first-line treatment for patients with these disease entities," Dr. Mathias J. Rummel said during a press conference at the annual meeting of the American Society of Clinical Oncology.

Bendamustine is marketed in the United States as Treanda (Cephalon). Bendamustine was developed 50 years ago in East Germany, Dr. Rummel said. Only after the reunification of Germany did physicians in the West learn about the drug and begin to conduct clinical trials and to publish the results.

A large randomized trial of 514 evaluable patients treated in community and hospital-based oncology groups in Germany, StiL NHL1 compared progression-free survival for the two regimens in patients with follicular, Waldenstrom’s, marginal zone, small lymphocytic, or mantle cell lymphomas.

Patients in the bendamustine-rituximab group had a median of 69.5 months of progression-free survival compared with 31.2 months with CHOP-rituximab. The benefit with bendamustine-rituximab was maintained in all histological subtypes except marginal zone lymphoma.

In patients with normal levels of lactic dehydrogenase (62%), progression-free survival was significantly prolonged with bendamustine-rituximab compared with CHOP-rituximab (P less than .001). In those with elevated levels of LDH (38%), progression-free survival was numerically, but not significantly, increased with bendamustine-rituximab (P = .118).

In patients with follicular lymphoma, follicular lymphoma international prognostic index (FLIPI) subgroups defined by 0-2 factors (favorable) and 3-5 factors (unfavorable) had longer progression-free survival with bendamustine-rituximab than with CHOP-rituximab. The longer progression-free survival was significant for both the favorable (P = .043) and unfavorable (P = .068) FLIPI subgroups.

Patients in the study were randomized for a maximum of six cycles to either bendamustine (90 mg/m² on day 1 and 2) and rituximab (375 mg/m² on day 1) or to CHOP-rituximab (cyclophosphamide 750 mg/m² on day 1, doxorubicin 50 mg/m² on day 1, vincristine 1.4 mg/m² on day 1, and prednisone 100 mg on days 1-5), and rituximab (375 mg/m² on day 1), according to Dr. Rummel of the University Hospital Giessen (Germany).

In the bendamustine-rituximab group, 74 salvage treatments had been initiated. In the CHOP-rituximab group, 116 salvage treatments were initiated. Of those in the CHOP-rituximab group, 52 patients received bendamustine-rituximab as a salvage regimen. Overall survival did not differ between the treatment arms, with 43 and 45 deaths in the two groups, respectively. Secondary malignancies were observed in 20 patients in the bendamustine-rituximab group compared with 23 in the CHOP-rituximab group, with 1 hematologic malignancy in each group (1 case of myelodysplastic syndrome in the bendamustine-rituximab group and 1 case of acute myelogenous leukemia in the CHOP-rituximab group).

Grade 3/4 hematotoxicities were significantly lower in the 261 patients in the bendamustine-rituximab group than in the 253 in the CHOP-rituximab group (P less than .0001). The percentage of cycles associated with leukopenia was 12% for bendamustine-rituximab patients and 38% for CHOP-rituximab patients. The percentage of cycles associated with neutropenia was nearly 11% with bendamustine-rituximab and more than 46% with CHOP-rituximab. The percentage of cycles that necessitated administration of granulocyte colony-stimulating factor (G-CSF) was 4% with bendamustine-rituximab and 20% with CHOP-rituximab. The rates of anemia and thrombocytopenia were comparable and low (less than 2% of cycles) for both regimens.

Importantly, alopecia did not occur with bendamustine-rituximab but was nearly universal with CHOP-rituximab, Dr. Rummel said. Paresthesias were noted in 18 of 261 bendamustine-rituximab patients and 73 of 253 CHOP-rituximab patients; stomatitis was seen in 16 and 73 patients, respectively. Both differences were significant (P less than .0001).

Conversely, the bendamustine-treated patients had more erythema (42 of 261 bendamustine-rituximab patients vs. 23 of 253 CHOP-rituximab patients) and allergic reactions (40 vs. 15, respectively). These were not dose-limiting toxicities. Infectious complications were frequent, and affected 96 bendamustine and 127 CHOP patients.

Next steps include a new trial called MAINTAIN that will examine rituximab maintenance therapy in 591 patients treated with bendamustine and rituximab. Patients will receive 2 years of rituximab maintenance therapy and will then be randomized to either observation or 2 more years of rituximab.

Dr. Rummel receives honoraria and research funding from Mundipharma and Roche.

Lenalidomide maintenance therapy delayed recurrences significantly when given to patients newly diagnosed with multiple myeloma in a trio of clinical trials that reported much-anticipated outcomes May 9 in the New England Journal of Medicine.

Only one trial showed a gain in overall survival, however, and the prospect of lenalidomide (Revlimid) maintenance becoming a standard of care remains uncertain despite the substantial benefit clearly demonstrated in these multicenter, double-blind, placebo-controlled phase III studies.

Notably, investigators reported that prolonged administration of lenalidomide was associated with an increased incidence of second cancers in patients who had undergone stem cell transplantation. This led the Food and Drug Administration to add a warning to the drug’s label on May 7 after a yearlong analysis of early data from the trials.

In addition, a bevy of new drugs, both approved and in the pipeline, has changed the course of multiple myeloma from one with a short life expectancy to that of a chronic disease, with most patients embarking on second-line therapies after experiencing recurrences within 3 years of initial treatment.

"It remains to be determined whether the incorporation of other new agents with lenalidomide will further increase the time to disease progression and overall survival," Dr. Philip L. McCarthy and his coauthors wrote at the conclusion of their report on the one trial that showed a benefit in overall survival.

Two trials compared maintenance lenalidomide with placebo in patients who achieved stable disease or better after stem cell transplantation. The third trial focused on an older group of patients that was not eligible for transplantation. All were stopped early after achieving their goals.

Crossover Did Not Erase Benefit

The Cancer and Leukemia Group B (CALGB) trial reported by Dr. McCarthy, of the Roswell Park Cancer Institute in Buffalo, N.Y., and his associates randomized 460 patients up to 70 years of age after stem cell transplantation. Patients in the lenalidomide arm started at 10 mg daily, and doses ranged from 5 to 15 mg until disease progression.

When the study was unblinded in December 2009, disease progression or death had occurred in 44% of the placebo group, but only 20% of patients on lenalidomide maintenance (hazard ratio, 0.37; P less than .001). Investigators reported that median time to progression was nearly twice as long with lenalidomide – 39 months vs. 21 months (P less than .001). At that point the study’s primary end point – time to progression – had been met, and 86 of 128 eligible patients in the placebo group began to receive lenalidomide maintenance.

Despite this crossover, lenalidomide maintenance continued to demonstrate a significant advantage at a median follow-up as of Oct. 31, 2011. By then, investigators reported, only 37% of the lenalidomide group had disease progression or death, compared with 58% of the placebo group (HR, 0.48). Median time to progression reached 46 months in the lenalidomide group vs. 27 months in the placebo arm (P less than .001), according to the new report.

The 3-year rate of freedom from progression or death was higher with lenalidomide maintenance (66% vs. 39%), as was the overall survival rate (88% vs. 80%, HR 0.62) (N. Engl. J. Med. 2012;366:1770-81).

Younger Group in IFM Trial

Dr. Michel Attal of Hôpital Purpan in Toulouse, France, and his colleagues from the Intergroupe Francophone du Myélome (IFM) conducted a similar trial in a population of 614 patients under age 65 whose disease had not progressed after stem cell transplantation. All patients received two 28-day cycles of consolidation treatment with lenalidomide (25 mg daily on days 121) followed by maintenance with placebo or lenalidomide (10 mg daily for 3 months, after which the dose could be increased to 15 mg if tolerated) until disease progression.

At the time the study was unblinded at a median follow-up of 30 months in July 2010, median progression-free survival was nearly twice as long with lenalidomide maintenance – 41 months, compared with 23 months with a placebo (HR, 0.50; P less than .001). Overall survival was similar between the groups, and neither group had reached median overall survival.

By October 2011, median follow-up from time of randomization had reached 45 months, and the probability of surviving without progression 4 years after randomization was still about double with lenalidomide: 43% vs. 22% (HR, 0.50; P less than .001).

The overall survival rate was still similar, however, at 73% with lenalidomide and 75% with placebo. These survival rates are high, the authors noted, and longer follow-up may show an advantage for lenalidomide maintenance.

"Together with the findings reported by McCarthy et al., our data support the use of lenalidomide maintenance therapy after high-dose chemotherapy and autologous hematopoietic stem-cell transplantation in patients with myeloma, but the impressive benefits must be weighed against the increased risks," said Dr. Attal and his coauthors (N. Engl. J. Med. 2012;366:1782-91).

Older Patients Ineligible for Transplant

Dr. Antonio Palumbo of the University of Turin, Italy, and his coinvestigators from the Multiple Myeloma-015 (MM-015) trial also explored continuous lenalidomide, but in a population of 459 patients aged 65 years and older who were not eligible for stem cell transplantation.

Patients were randomized to three groups: One group received induction therapy with melphalan, prednisone, and lenalidomide followed by lenalidomide maintenance (MPR-R); the second received MPR followed by placebo maintenance; and the third received only melphalan and prednisone (MP) followed by placebo. Investigators reported that about two-thirds of patients completed their induction regimens.

Median progression-free survival, the primary end point, was significantly longer in the group that received lenalidomide maintenance (31 months) than in the groups that received MPR with placebo (14 months) or MP without any lenalidomide in the induction and maintenance phases (13 months).

In a landmark analysis that looked at progression-free survival from the start of maintenance therapy, the median reached 26 months with lenalidomide vs. 7 months with placebo, with a hazard ratio of 0.34 for MPR-R vs. MPR (P less than .001).

Greater benefit was seen in patients 65-75 years of age, with median progression-free survival of 31 months with MPR-R, 15 months with MPR, and 12 months with MP. In patients over age 75, the medians were 19 months, 12 months, and 15 months, respectively.

Median overall survival at 3 years was not significantly different, reaching 70% with MPR-R, 62% with MPR, and 66% with MP.

"Altogether, these results confirm the benefits of maintenance therapy with respect to progression-free survival. The influence on overall survival remains unclear," concluded Dr. Palumbo and his coauthors (N. Engl. J. Med. 2012;366:1759-69).

Secondary Malignancies

In all three studies lenalidomide was associated with higher rates of secondary primary cancers.

• The rate was 8% in the lenalidomide group vs. 3% in the placebo group in the CALGB study.

• The IFM investigators calculated the incidence as 3.1 per 100 patient-years in their lenalidomide group vs. 1.2 per 100 patient-years with placebo (P = .002).

• In the MM-015 study, the 3-year rate was 7% with MPR-R, 7% with MPR, and 3% with MP. The increased risk was "mainly confined to acute myeloid leukemia or myelodysplastic syndromes, and is observed when lenalidomide is given with or after melphalan," the investigators wrote.

Other Adverse Events

Hematologic toxicity dominated the adverse event reports from all three studies.

• In the CALBG trial, grade 3 and 4 hematologic side effects were significantly more common with lenalidomide maintenance, as were grade 3 nonhematologic events. The most pronounced was neutropenia in 45% of the lenalidomide group vs. 15% of the placebo group (P less than .001).

• The IFM investigators also reported that grade 3 or 4 hematologic events were more frequent with lenalidomide than with placebo (58% vs. 23%, P less than .001), as were thromboembolic events (6% vs. 2%, P = .01).

• Similarly, the MM-015 group found that the most frequent adverse events were hematologic, with grade 4 neutropenia occurring in 35% of patients given lenalidomide. Nonhematologic events, including deep vein thrombosis, occurred at low rates, however, according to Dr. Palumbo and his coauthors. "Lenalidomide maintenance was associated with little evidence of cumulative toxic effects," they said.

How the safety profiles will influence adoption of lenalidomide maintenance is uncertain. "A major concern during maintenance therapy is toxicity that limits long-term use and the ability to receive future treatment after disease progression or that results in life-threatening disorders," noted Dr. McCarthy and his coauthors.

The National Cancer Institute supported the CALGB trial. Celgene, maker of lenalidomide, provided support for the IFM and MM-015 studies. The IFM trial also received support from the Programme Hospitalier de Recherche Clinique and the Swiss Group for Clinical Cancer Research (SAKK). Disclosure forms filed by individual investigators are posted at http://www.nejm.org.

Lenalidomide maintenance therapy delayed recurrences significantly when given to patients newly diagnosed with multiple myeloma in a trio of clinical trials that reported much-anticipated outcomes May 9 in the New England Journal of Medicine.

Only one trial showed a gain in overall survival, however, and the prospect of lenalidomide (Revlimid) maintenance becoming a standard of care remains uncertain despite the substantial benefit clearly demonstrated in these multicenter, double-blind, placebo-controlled phase III studies.

Notably, investigators reported that prolonged administration of lenalidomide was associated with an increased incidence of second cancers in patients who had undergone stem cell transplantation. This led the Food and Drug Administration to add a warning to the drug’s label on May 7 after a yearlong analysis of early data from the trials.

In addition, a bevy of new drugs, both approved and in the pipeline, has changed the course of multiple myeloma from one with a short life expectancy to that of a chronic disease, with most patients embarking on second-line therapies after experiencing recurrences within 3 years of initial treatment.

"It remains to be determined whether the incorporation of other new agents with lenalidomide will further increase the time to disease progression and overall survival," Dr. Philip L. McCarthy and his coauthors wrote at the conclusion of their report on the one trial that showed a benefit in overall survival.

Two trials compared maintenance lenalidomide with placebo in patients who achieved stable disease or better after stem cell transplantation. The third trial focused on an older group of patients that was not eligible for transplantation. All were stopped early after achieving their goals.

Crossover Did Not Erase Benefit

The Cancer and Leukemia Group B (CALGB) trial reported by Dr. McCarthy, of the Roswell Park Cancer Institute in Buffalo, N.Y., and his associates randomized 460 patients up to 70 years of age after stem cell transplantation. Patients in the lenalidomide arm started at 10 mg daily, and doses ranged from 5 to 15 mg until disease progression.

When the study was unblinded in December 2009, disease progression or death had occurred in 44% of the placebo group, but only 20% of patients on lenalidomide maintenance (hazard ratio, 0.37; P less than .001). Investigators reported that median time to progression was nearly twice as long with lenalidomide – 39 months vs. 21 months (P less than .001). At that point the study’s primary end point – time to progression – had been met, and 86 of 128 eligible patients in the placebo group began to receive lenalidomide maintenance.

Despite this crossover, lenalidomide maintenance continued to demonstrate a significant advantage at a median follow-up as of Oct. 31, 2011. By then, investigators reported, only 37% of the lenalidomide group had disease progression or death, compared with 58% of the placebo group (HR, 0.48). Median time to progression reached 46 months in the lenalidomide group vs. 27 months in the placebo arm (P less than .001), according to the new report.

The 3-year rate of freedom from progression or death was higher with lenalidomide maintenance (66% vs. 39%), as was the overall survival rate (88% vs. 80%, HR 0.62) (N. Engl. J. Med. 2012;366:1770-81).

Younger Group in IFM Trial

Dr. Michel Attal of Hôpital Purpan in Toulouse, France, and his colleagues from the Intergroupe Francophone du Myélome (IFM) conducted a similar trial in a population of 614 patients under age 65 whose disease had not progressed after stem cell transplantation. All patients received two 28-day cycles of consolidation treatment with lenalidomide (25 mg daily on days 121) followed by maintenance with placebo or lenalidomide (10 mg daily for 3 months, after which the dose could be increased to 15 mg if tolerated) until disease progression.

At the time the study was unblinded at a median follow-up of 30 months in July 2010, median progression-free survival was nearly twice as long with lenalidomide maintenance – 41 months, compared with 23 months with a placebo (HR, 0.50; P less than .001). Overall survival was similar between the groups, and neither group had reached median overall survival.

By October 2011, median follow-up from time of randomization had reached 45 months, and the probability of surviving without progression 4 years after randomization was still about double with lenalidomide: 43% vs. 22% (HR, 0.50; P less than .001).

The overall survival rate was still similar, however, at 73% with lenalidomide and 75% with placebo. These survival rates are high, the authors noted, and longer follow-up may show an advantage for lenalidomide maintenance.

"Together with the findings reported by McCarthy et al., our data support the use of lenalidomide maintenance therapy after high-dose chemotherapy and autologous hematopoietic stem-cell transplantation in patients with myeloma, but the impressive benefits must be weighed against the increased risks," said Dr. Attal and his coauthors (N. Engl. J. Med. 2012;366:1782-91).

Older Patients Ineligible for Transplant

Dr. Antonio Palumbo of the University of Turin, Italy, and his coinvestigators from the Multiple Myeloma-015 (MM-015) trial also explored continuous lenalidomide, but in a population of 459 patients aged 65 years and older who were not eligible for stem cell transplantation.

Patients were randomized to three groups: One group received induction therapy with melphalan, prednisone, and lenalidomide followed by lenalidomide maintenance (MPR-R); the second received MPR followed by placebo maintenance; and the third received only melphalan and prednisone (MP) followed by placebo. Investigators reported that about two-thirds of patients completed their induction regimens.

Median progression-free survival, the primary end point, was significantly longer in the group that received lenalidomide maintenance (31 months) than in the groups that received MPR with placebo (14 months) or MP without any lenalidomide in the induction and maintenance phases (13 months).

In a landmark analysis that looked at progression-free survival from the start of maintenance therapy, the median reached 26 months with lenalidomide vs. 7 months with placebo, with a hazard ratio of 0.34 for MPR-R vs. MPR (P less than .001).

Greater benefit was seen in patients 65-75 years of age, with median progression-free survival of 31 months with MPR-R, 15 months with MPR, and 12 months with MP. In patients over age 75, the medians were 19 months, 12 months, and 15 months, respectively.

Median overall survival at 3 years was not significantly different, reaching 70% with MPR-R, 62% with MPR, and 66% with MP.

"Altogether, these results confirm the benefits of maintenance therapy with respect to progression-free survival. The influence on overall survival remains unclear," concluded Dr. Palumbo and his coauthors (N. Engl. J. Med. 2012;366:1759-69).

Secondary Malignancies

In all three studies lenalidomide was associated with higher rates of secondary primary cancers.

• The rate was 8% in the lenalidomide group vs. 3% in the placebo group in the CALGB study.

• The IFM investigators calculated the incidence as 3.1 per 100 patient-years in their lenalidomide group vs. 1.2 per 100 patient-years with placebo (P = .002).

• In the MM-015 study, the 3-year rate was 7% with MPR-R, 7% with MPR, and 3% with MP. The increased risk was "mainly confined to acute myeloid leukemia or myelodysplastic syndromes, and is observed when lenalidomide is given with or after melphalan," the investigators wrote.

Other Adverse Events

Hematologic toxicity dominated the adverse event reports from all three studies.

• In the CALBG trial, grade 3 and 4 hematologic side effects were significantly more common with lenalidomide maintenance, as were grade 3 nonhematologic events. The most pronounced was neutropenia in 45% of the lenalidomide group vs. 15% of the placebo group (P less than .001).

• The IFM investigators also reported that grade 3 or 4 hematologic events were more frequent with lenalidomide than with placebo (58% vs. 23%, P less than .001), as were thromboembolic events (6% vs. 2%, P = .01).

• Similarly, the MM-015 group found that the most frequent adverse events were hematologic, with grade 4 neutropenia occurring in 35% of patients given lenalidomide. Nonhematologic events, including deep vein thrombosis, occurred at low rates, however, according to Dr. Palumbo and his coauthors. "Lenalidomide maintenance was associated with little evidence of cumulative toxic effects," they said.

How the safety profiles will influence adoption of lenalidomide maintenance is uncertain. "A major concern during maintenance therapy is toxicity that limits long-term use and the ability to receive future treatment after disease progression or that results in life-threatening disorders," noted Dr. McCarthy and his coauthors.

The National Cancer Institute supported the CALGB trial. Celgene, maker of lenalidomide, provided support for the IFM and MM-015 studies. The IFM trial also received support from the Programme Hospitalier de Recherche Clinique and the Swiss Group for Clinical Cancer Research (SAKK). Disclosure forms filed by individual investigators are posted at http://www.nejm.org.

Lenalidomide maintenance therapy delayed recurrences significantly when given to patients newly diagnosed with multiple myeloma in a trio of clinical trials that reported much-anticipated outcomes May 9 in the New England Journal of Medicine.

Only one trial showed a gain in overall survival, however, and the prospect of lenalidomide (Revlimid) maintenance becoming a standard of care remains uncertain despite the substantial benefit clearly demonstrated in these multicenter, double-blind, placebo-controlled phase III studies.

Notably, investigators reported that prolonged administration of lenalidomide was associated with an increased incidence of second cancers in patients who had undergone stem cell transplantation. This led the Food and Drug Administration to add a warning to the drug’s label on May 7 after a yearlong analysis of early data from the trials.

In addition, a bevy of new drugs, both approved and in the pipeline, has changed the course of multiple myeloma from one with a short life expectancy to that of a chronic disease, with most patients embarking on second-line therapies after experiencing recurrences within 3 years of initial treatment.

"It remains to be determined whether the incorporation of other new agents with lenalidomide will further increase the time to disease progression and overall survival," Dr. Philip L. McCarthy and his coauthors wrote at the conclusion of their report on the one trial that showed a benefit in overall survival.

Two trials compared maintenance lenalidomide with placebo in patients who achieved stable disease or better after stem cell transplantation. The third trial focused on an older group of patients that was not eligible for transplantation. All were stopped early after achieving their goals.

Crossover Did Not Erase Benefit

The Cancer and Leukemia Group B (CALGB) trial reported by Dr. McCarthy, of the Roswell Park Cancer Institute in Buffalo, N.Y., and his associates randomized 460 patients up to 70 years of age after stem cell transplantation. Patients in the lenalidomide arm started at 10 mg daily, and doses ranged from 5 to 15 mg until disease progression.

When the study was unblinded in December 2009, disease progression or death had occurred in 44% of the placebo group, but only 20% of patients on lenalidomide maintenance (hazard ratio, 0.37; P less than .001). Investigators reported that median time to progression was nearly twice as long with lenalidomide – 39 months vs. 21 months (P less than .001). At that point the study’s primary end point – time to progression – had been met, and 86 of 128 eligible patients in the placebo group began to receive lenalidomide maintenance.

Despite this crossover, lenalidomide maintenance continued to demonstrate a significant advantage at a median follow-up as of Oct. 31, 2011. By then, investigators reported, only 37% of the lenalidomide group had disease progression or death, compared with 58% of the placebo group (HR, 0.48). Median time to progression reached 46 months in the lenalidomide group vs. 27 months in the placebo arm (P less than .001), according to the new report.

The 3-year rate of freedom from progression or death was higher with lenalidomide maintenance (66% vs. 39%), as was the overall survival rate (88% vs. 80%, HR 0.62) (N. Engl. J. Med. 2012;366:1770-81).

Younger Group in IFM Trial

Dr. Michel Attal of Hôpital Purpan in Toulouse, France, and his colleagues from the Intergroupe Francophone du Myélome (IFM) conducted a similar trial in a population of 614 patients under age 65 whose disease had not progressed after stem cell transplantation. All patients received two 28-day cycles of consolidation treatment with lenalidomide (25 mg daily on days 121) followed by maintenance with placebo or lenalidomide (10 mg daily for 3 months, after which the dose could be increased to 15 mg if tolerated) until disease progression.

At the time the study was unblinded at a median follow-up of 30 months in July 2010, median progression-free survival was nearly twice as long with lenalidomide maintenance – 41 months, compared with 23 months with a placebo (HR, 0.50; P less than .001). Overall survival was similar between the groups, and neither group had reached median overall survival.

By October 2011, median follow-up from time of randomization had reached 45 months, and the probability of surviving without progression 4 years after randomization was still about double with lenalidomide: 43% vs. 22% (HR, 0.50; P less than .001).

The overall survival rate was still similar, however, at 73% with lenalidomide and 75% with placebo. These survival rates are high, the authors noted, and longer follow-up may show an advantage for lenalidomide maintenance.

"Together with the findings reported by McCarthy et al., our data support the use of lenalidomide maintenance therapy after high-dose chemotherapy and autologous hematopoietic stem-cell transplantation in patients with myeloma, but the impressive benefits must be weighed against the increased risks," said Dr. Attal and his coauthors (N. Engl. J. Med. 2012;366:1782-91).

Older Patients Ineligible for Transplant

Dr. Antonio Palumbo of the University of Turin, Italy, and his coinvestigators from the Multiple Myeloma-015 (MM-015) trial also explored continuous lenalidomide, but in a population of 459 patients aged 65 years and older who were not eligible for stem cell transplantation.

Patients were randomized to three groups: One group received induction therapy with melphalan, prednisone, and lenalidomide followed by lenalidomide maintenance (MPR-R); the second received MPR followed by placebo maintenance; and the third received only melphalan and prednisone (MP) followed by placebo. Investigators reported that about two-thirds of patients completed their induction regimens.

Median progression-free survival, the primary end point, was significantly longer in the group that received lenalidomide maintenance (31 months) than in the groups that received MPR with placebo (14 months) or MP without any lenalidomide in the induction and maintenance phases (13 months).

In a landmark analysis that looked at progression-free survival from the start of maintenance therapy, the median reached 26 months with lenalidomide vs. 7 months with placebo, with a hazard ratio of 0.34 for MPR-R vs. MPR (P less than .001).

Greater benefit was seen in patients 65-75 years of age, with median progression-free survival of 31 months with MPR-R, 15 months with MPR, and 12 months with MP. In patients over age 75, the medians were 19 months, 12 months, and 15 months, respectively.

Median overall survival at 3 years was not significantly different, reaching 70% with MPR-R, 62% with MPR, and 66% with MP.

"Altogether, these results confirm the benefits of maintenance therapy with respect to progression-free survival. The influence on overall survival remains unclear," concluded Dr. Palumbo and his coauthors (N. Engl. J. Med. 2012;366:1759-69).

Secondary Malignancies

In all three studies lenalidomide was associated with higher rates of secondary primary cancers.

• The rate was 8% in the lenalidomide group vs. 3% in the placebo group in the CALGB study.

• The IFM investigators calculated the incidence as 3.1 per 100 patient-years in their lenalidomide group vs. 1.2 per 100 patient-years with placebo (P = .002).

• In the MM-015 study, the 3-year rate was 7% with MPR-R, 7% with MPR, and 3% with MP. The increased risk was "mainly confined to acute myeloid leukemia or myelodysplastic syndromes, and is observed when lenalidomide is given with or after melphalan," the investigators wrote.

Other Adverse Events

Hematologic toxicity dominated the adverse event reports from all three studies.

• In the CALBG trial, grade 3 and 4 hematologic side effects were significantly more common with lenalidomide maintenance, as were grade 3 nonhematologic events. The most pronounced was neutropenia in 45% of the lenalidomide group vs. 15% of the placebo group (P less than .001).

• The IFM investigators also reported that grade 3 or 4 hematologic events were more frequent with lenalidomide than with placebo (58% vs. 23%, P less than .001), as were thromboembolic events (6% vs. 2%, P = .01).

• Similarly, the MM-015 group found that the most frequent adverse events were hematologic, with grade 4 neutropenia occurring in 35% of patients given lenalidomide. Nonhematologic events, including deep vein thrombosis, occurred at low rates, however, according to Dr. Palumbo and his coauthors. "Lenalidomide maintenance was associated with little evidence of cumulative toxic effects," they said.

How the safety profiles will influence adoption of lenalidomide maintenance is uncertain. "A major concern during maintenance therapy is toxicity that limits long-term use and the ability to receive future treatment after disease progression or that results in life-threatening disorders," noted Dr. McCarthy and his coauthors.

The National Cancer Institute supported the CALGB trial. Celgene, maker of lenalidomide, provided support for the IFM and MM-015 studies. The IFM trial also received support from the Programme Hospitalier de Recherche Clinique and the Swiss Group for Clinical Cancer Research (SAKK). Disclosure forms filed by individual investigators are posted at http://www.nejm.org.