FDA Alerts

In cooperation with the Food and Drug Administration (FDA), and as a service to our members, HOPA will periodically distribute information about newly approved therapies for cancer patients.  This helps FDA to inform oncologists and professionals in oncology-related fields of recent approvals in a timely manner.  Included in the email from the FDA will be a link to the product label, which will provide the relevant clinical information on the indication, contraindications, dosing, and safety.  In sending this information, HOPA does not endorse any product or therapy and does not take any position on the safety or efficacy of the product or therapy described.

Brentuximab Vedotin (Adcetris™ for Injection)

The following is a message from the FDA's Office of Oncology Drug Products Director, Dr. Richard Pazdur:

On August 19, 2011, the U. S. Food and Drug Administration granted accelerated approval to brentuximab vedotin (Adcetris™ for Injection, Seattle Genetics, Inc.) for two indications:  

• The treatment of patients with Hodgkin lymphoma after failure of autologous stem cell transplant (ASCT) or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not ASCT candidates.
• The treatment of patients with systemic anaplastic large cell lymphoma (ALCL) after failure of at least one prior multi-agent chemotherapy regimen.

The accelerated approval of the Hodgkin lymphoma indication was based on a single-arm, multicenter, clinical trial (Trial SG035-0003) to evaluate the objective response rate (ORR) of brentuximab vedotin as a single agent. Patients who enrolled in the trial (n = 102) had CD30-positive Hodgkin Lymphoma that relapsed after ASCT.

The primary efficacy endpoint in the Hodgkin lymphoma trial, ORR by Independent Review Facility, was 73% (95% CI: 65, 83) with a median duration of 6.7 months (95% CI: 4, 14.8). Complete Remission (CR) rate was 32% (95% CI: 23.3, 42.3) with a median duration of 20.5 months (95% CI: 12, NE). Partial Remission (PR) rate was 40% (95% CI: 31.5, 49.4) with a median duration of 3.5 months (95% CI: 2.2, 4.1).

The accelerated approval for the systemic ALCL indication was based on a single-arm, multicenter, clinical trial (Trial SG035-0004) enrolling 58 patients who had CD30-positive systemic ALCL and had previously received front-line, multi-agent chemotherapy regimens.

The primary efficacy endpoint in the systemic ALCL trial, ORR by Independent Review Facility, was 86% (95% CI: 77, 95) with a median duration of 12.6 months (95% CI: 5.7, NE). CR rate was 57% (95% CI: 44, 70) with a median duration of 13.2 months (95% CI: 10.8, NE). PR rate was 29% (95% CI: 18, 41) with a median duration of 2.1 months (95% CI: 1.3, 5.7).

The most common adverse reactions (≥20%) noted in both trials were neutropenia, peripheral sensory neuropathy, fatigue, nausea, anemia, upper respiratory tract infection, diarrhea, pyrexia, rash, thrombocytopenia, cough and vomiting. Serious adverse events (SAEs) were reported in 31% of patients. The most common (>2%) SAEs reported were peripheral motor neuropathy, urinary tract infection, and abdominal pain. Refer to the prescribing information link below for further details of safety profiles of the individual trials.

The recommended dose and schedule for both indications is 1.8 mg/kg administered as an intravenous infusion over 30 minutes every 3 weeks. Treatment may be continued until maximum of 16 cycles, until disease progression, or unacceptable toxicity.   

  Full prescribing information, including clinical trial information, safety, dosing, drug-drug interactions and contraindications is available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/125388s000,125399s000lbl.pdf

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA's MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088). 

Vemurafenib tablets (Zelboraftm)

The following is a message from the FDA's Office of Oncology Drug Products Director, Dr. Richard Pazdur:

On August 17, 2011, the U. S. Food and Drug Administration approved vemurafenib tablets (ZELBORAFTM, Hoffmann-La Roche Inc.) for the treatment of patients with unresectable or metastatic melanoma with the BRAFV600E mutation as detected by an FDA-approved test.  The approval was based primarily on an international, randomized, open-label trial in patients with previously untreated metastatic or unresectable melanoma with the BRAFV600E mutation as detected by the cobas® 4800 BRAF V600 Mutation Test (Roche Molecular Systems, Inc.). This companion diagnostic test was approved by the FDA concurrently with vemurafenib's approval.

The trial enrolled 675 patients; 337 patients were assigned to vemurafenib, 960 mg orally twice daily, and 338 were assigned to dacarbazine, 1000 mg/m² intravenously, every three weeks. Treatment continued until disease progression, unacceptable toxicity, and/or consent withdrawal. All patients had an ECOG performance status of 0 or 1, and 95% of patients had metastatic disease. The major efficacy outcome measures of the trial were overall survival (OS) and investigator-assessed progression-free survival (PFS). Other outcome measures included confirmed investigator-assessed best overall response rate.

The median follow-up at the time of the overall survival analysis was 6.2 and 4.5 months for the vemurafenib and dacarbazine arms, respectively. Overall survival was significantly improved in patients receiving vemurafenib compared to those receiving dacarbazine (HR = 0.44; 95% CI: 0.33, 0.59; p < .0001, log-rank test). The median survival of patients receiving vemurafenib had not been reached (95% CI: 9.6 months, not reached) and was 7.9 months (95% CI: 7.3, 9.6) for those receiving dacarbazine.

Progression-free survival (PFS) was also significantly improved in patients receiving vemurafenib (HR = 0.26; 95% CI: 0.20, 0.33; p < .0001, log-rank test). The median PFS was 5.3 (95% CI: 4.9, 6.6) and 1.6 months (95% CI: 1.6, 1.7) in the vemurafenib and dacarbazine arms, respectively. Overall response rate (complete plus partial response rates) was 48.4% (95% CI: 41.6%, 55.2%) and 5.5% (95% CI: 2.8%, 9.3%) in the vemurafenib and dacarbazine arms, respectively.

Vemurafenib was also evaluated in a single-arm, multicenter trial that enrolled 132 patients with BRAFV600E mutation-positive metastatic melanoma who had received at least one prior systemic therapy. An independent review of treatment responses demonstrated a confirmed best overall response rate of 52% (95% CI: 43%, 61%), with a median response duration of 6.5 months (95% CI: 5.6, not reached).

The most common adverse reactions (≥30%) in patients treated with vemurafenib were arthralgia, rash, alopecia, fatigue, photosensitivity reaction, and nausea. Cutaneous squamous cell carcinomas (cuSCC), including squamous cell carcinomas of the skin and keratoacanthomas, were detected in approximately 24% of patients treated with vemurafenib. CuSCCs were managed with excision in clinical trials, and patients were able to continue treatment without dose adjustment. Other adverse reactions, sometimes severe, reported in vemurafenib-treated patients included hypersensitivity, Stevens-Johnson syndrome, toxic epidermal necrolysis, uveitis, QT prolongation, and liver enzyme laboratory abnormalities.

The recommended dose of vemurafenib is 960 mg, orally twice daily administered approximately 12 hours apart, with or without a meal.

Confirmation of BRAFV600E mutation-positive melanoma using an FDA-approved test is required before treatment with vemurafenib. Vemurafenib is not recommended for use in patients with wild-type BRAF melanoma. The approval also contains a Medication Guide to inform health care professionals and patients of vemurafenib's potential risks.

Full prescribing information, including clinical trial information, safety, dosing, drug-drug interactions and contraindications is available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/202429s000lbl.pdf 

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA's MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

Afinitor^® Tablets

The following is a message from the FDA's Office of Oncology Drug Products Director, Dr. Richard Pazdur:

On May 5, 2011, the U. S. Food and Drug Administration approved everolimus (Afinitor^® Tablets, Novartis Pharmaceuticals Corporation), for the treatment of progressive neuroendocrine tumors of pancreatic origin (PNET) in patients with unresectable, locally advanced or metastatic disease. The safety and effectiveness of everolimus in the treatment of patients with carcinoid tumors have not been established.

The approval was based on a randomized, controlled trial of everolimus 10 mg/d (n=207) versus placebo (n=203) in patients with unresectable, locally advanced or metastatic pancreatic neuroendocrine tumors. Patients were stratified by prior cytotoxic chemotherapy and by WHO performance status. Treatment with somatostatin analogs was allowed as part of best supportive care. The primary endpoint was progression-free survival (PFS) as assessed by the investigator. After documented radiological progression, patients on the placebo arm could cross over to everolimus. Among the 203 patients randomized to placebo, 73% crossed over to everolimus. Secondary endpoints included overall survival, response rate, and response duration.

The median PFS was 11.0 and 4.6 months in the everolimus and placebo arms, respectively [HR 0.35 (95% CI: 0.27, 0.45), p < 0.001]. An improvement in PFS was observed across all patient subgroups, irrespective of prior somatostatin analog use. An interim analysis showed no difference in overall survival [HR 1.05 (95% CI: 0.71, 1.55)].

Investigator-determined response rate was 4.8% in the everolimus arm. There were no complete responses.

Safety data were evaluated in 204 patients who received everolimus during the double-blind portion of the randomized trial described above and in 858 patients with advanced neuroendocrine tumors in the safety database. The most common (> 30%) grade 1-4 adverse reactions were stomatitis, rash, diarrhea, fatigue, edema, abdominal pain, nausea, fever, and headache. The most common (> 5%) grade 3-4 adverse reactions were stomatitis and diarrhea. The most common (> 3%) grade 3-4 laboratory abnormalities were hyperglycemia, lymphopenia, decreased hemoglobin, hypophosphatemia, increased alkaline phosphatase, neutropenia, increased aspartate transaminase (AST), potassium decreased, and thrombocytopenia.

Deaths occurred in 7 patients on everolimus and 1 patient on placebo. Causes of death on the everolimus arm included acute renal failure, acute respiratory distress, cardiac arrest, death (cause unknown), hepatic failure, pneumonia, and sepsis. After crossover to open-label everolimus, there were 3 additional deaths, one due to hypoglycemia and cardiac arrest in a patient with insulinoma, one due to MI with CHF, and the other due to sudden death. Adverse events resulted in permanent discontinuation in 20% and 6% of patients in the everolimus and placebo arms, respectively. Dose delays and/or reductions were necessary in 61% of everolimus patients and 29% of placebo patients. Opportunistic infections in patients with advanced neuroendocrine tumors included hepatitis B reactivation (resulting in death), mycobacterial infection, and invasive aspergillus. Pneumonitis was seen in 11% of patients (1.7% were grade 3/4) in the safety database.

The recommended dose and schedule for everolimus is10 mg orally each day. Patients with severe or intolerable adverse reactions may require temporary dose reductions to 5 mg/daily or dose interruption.

Full prescribing information, including clinical trial information, safety, dosing, drug-drug interactions and contraindications is available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022344s9s10lbl.pdf

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA's MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

Zytiga^TM

The following is a message from the FDA's Office of Oncology Drug Products Director, Dr. Richard Pazdur:

On April 28, 2011, the U.S. Food and Drug Administration approved abiraterone acetate (Zytiga^TM Tablets, Centocor Ortho Biotech, Inc.) for use in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) who have received prior chemotherapy containing docetaxel.

The approval is based on the results of a randomized, placebo-controlled, multicenter trial in 1195 patients with mCRPC previously treated with docetaxel-containing regimens. Patients were randomly allocated (2:1) to receive either abiraterone acetateorally at a dose of 1000 mg once daily (N=797) or placebo once daily (N=398). Patients in both arms (abiraterone acetate and placebo) received prednisone 5 mg orally twice daily. Treatment continued until disease progression (defined as a 25% increase in PSA over the patient's baseline/nadir together with protocol-defined radiographic progression and symptomatic or clinical progression), unacceptable toxicity, initiation of new treatment, or withdrawal. Patients with prior ketoconazole treatment for prostate cancer and a history of adrenal gland or pituitary disorders were excluded.

A pre-specified interim overall survival (OS) analysis was performed when 552 events had occurred. This analysis demonstrated a statistically significant improvement in OS in patients receiving abiraterone acetate compared to those on the placebo-containing arm (HR=0.646; 95% CI: 0.543, 0.768; p < 0.0001). The median OS was 14.8 versus 10.9 months in the abiraterone and placebo arm, respectively. An updated OS analysis, conducted after 775events, demonstrated a median OS of 15.8 versus 11.2 months in the abiraterone acetate and placebo-containing arms, respectively (HR=0.740; 95% CI: 0.638, 0.859).

The most common adverse reactions (> 5%) were joint swelling or discomfort, hypokalemia, edema, muscle discomfort, hot flush, diarrhea, urinary tract infection, cough, hypertension, arrhythmia, urinary frequency, nocturia, dyspepsia and upper respiratory tract infection. The most common adverse drug reactions resulting in drug discontinuation were increased aspartate aminotransferase and/or alanine aminotransferase, urosepsis and cardiac failure (each in < 1% of patients taking abiraterone).

The most common electrolyte imbalances in patients receiving abiraterone were hypokalemia (28%) and hypophosphatemia (24%). Following interruption of daily corticosteroids and/or with concurrent infection or stress, adrenocortical insufficiency (<1%) has been reported in clinical trials in patients receiving abiraterone acetate at the recommended dose in combination with prednisone.

Abiraterone acetate Cmax and exposure were increased up to 17-fold and 10-fold higher, respectively, when a single dose was administered with a meal compared to a fasting state.

The recommended dose and schedule for abiraterone acetate is 1000 mg orally once daily in combination with prednisone 5 mg orally twice daily. Abiraterone acetateshould be taken on an empty stomach. No food should be consumed for at least two hours before the dose of abiraterone acetateis taken and for at least one hour after the abiraterone acetate dose.

Full prescribing information, including clinical trial information, safety, dosing, drug-drug interactions and contraindications is available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/202379lbl.pdf

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA's MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

Sylatron™

On March 29, 2011, the U. S. Food and Drug Administration approved peginterferon alfa-2b (Sylatron™, Schering Corporation, Kenilworth, NJ 07033), for the treatment of patients with melanoma with microscopic or gross nodal involvement within 84 days of definitive surgical resection including complete lymphadenectomy.

The approval was based on a single trial, EORTC 18991, an open label, multi-center trial enrolling 1256 patients. Patients who had been adequately surgically resected for their primary cutaneous melanoma and affected regional lymph nodes were randomized (1:1) to receive either Sylatron or observation for a 5 year period. Stratification factors included type of nodal involvement (microscopic versus gross), number of positive nodes (1, 2-4, 5 or more, or not assessed), Breslow primary thickness (less than 1.5 mm, ≥ 1.5 to 4 mm, ≥ 4 mm), ulceration of primary tumor (present or absent or unknown), sex, and study center. Patients were assessed for local and regional recurrence or distant metastases every three months for the first two years of treatment and subsequently every six months through the end of the trial. An independent review committee, blinded to randomization assignment and to information that would break the treatment blind, reviewed the case report form data to determine the occurrence, and the date of loco-regional recurrence, or distant metastasis.

The primary efficacy endpoint, relapse-free survival (RFS), was defined as the time to the earliest of local or regional recurrence, distant metastases, or death. Based on 696 RFS events, an improvement in RFS for Sylatron-treated patients [hazard ratio 0.82 (95% CI: 0.71, 0.96); unstratified log-rank p = 0.011] was observed. The estimated median RFS was 34.8 months (95% CI: 26.1, 47.4) and 25.5 months (95% CI: 19.6, 30.8) in the Sylatron and observation arms, respectively. Following 525 deaths on study, there was no difference in overall survival between the Sylatron and the observation arms [hazard ratio 0.98 (95% CI: 0.82, 1.16)].

Safety was evaluated in 608 Sylatron-treated patients in EORTC 18991. The most common (>60%) grade 1-4 adverse reactions experienced by Sylatron-treated patients were fatigue, increased ALT, increased AST, pyrexia, headache, anorexia, myalgia, nausea, chills, and injection site reactions. The most common serious adverse reactions occurring in Sylatron-treated patients were fatigue, increased ALT, increased AST, and pyrexia.

Thirty-three percent of patients receiving Sylatron discontinued treatment due to adverse reactions. The most common adverse reactions present at the time of treatment discontinuation were fatigue, depression, anorexia, increased ALT, increased AST, myalgia, nausea, headache, and pyrexia. Five deaths were reported within 30 days of the last Sylatron dose. Two were attributed to recurrent disease, two to cardiovascular disease possibly related to Sylatron, and one to an accident.

The recommended dose and schedule for Sylatron is 6 mcg/kg/week, subcutaneously for 8 doses, followed by 3 mcg/kg/week subcutaneously. The maximum treatment period is 5 years (260 weeks).

Full prescribing information, including clinical trial information, safety, dosing, drug-drug interactions and contraindications is available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/103949s5153lbl.pdf

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

YERVOY^®

On March 25, 2011, the U.S. Food and Drug Administration approved ipilimumab injection (YERVOY^®, Bristol-Myers Squibb Company) for the treatment of unresectable or metastatic melanoma.

The approval was based on a randomized (3:1:1), double-blind, double-dummy clinical trial (MDX010-20) in patients with unresectable or metastatic melanoma who had received at least one prior systemic treatment for melanoma. Overall survival (OS) was the trial's primary endpoint. Progression-free survival and best overall response rate were also assessed.

The clinical trial enrolled 676 patients with HLA–A2*0201 positive genotype. This HLA-A2*0201 genotype facilitated the immune presentation of the investigational tumor vaccine. The three treatment arms consisted of ipilimumab, 3 mg/kg intravenously, in combination with the tumor vaccine (n = 403), ipilimumab plus vaccine placebo (n = 137), and tumor vaccine with placebo (n = 136). The trial excluded patients with active autoimmune disease or those receiving systemic immunosuppression for organ transplantation.

The median age of the patients was 57 years with 29% of patients age 65 years or older. More than half the patients were male, 71% had M1c stage, 12% had histories of previously treated brain metastases, 98% had ECOG performance status of either 0 or 1, and 23% had received prior aldesleukin (IL-2).

Overall survival was longer with ipilimumab alone compared to tumor vaccine [HR 0.66 (95% CI: 0.51, 0.87), p = 0.0026] with median OS of 10 and 6 months, respectively, for ipilimumab alone and the vaccine arm. The trial also demonstrated a statistically significant improvement in OS for the combination of ipilimumab plus tumor vaccine compared to tumor vaccine alone [HR 0.68 (95% CI: 0.55, 0.85), p = 0.1114, log-rank test)] with median OS of 10 and 6 months, respectively. The best overall response rate (investigator assessed) was 10.9% (95% CI: 6.3%, 17.4%) in the ipilimumab arm, 5.7% (95% CI: 3.7%, 8.4%) in the combination of ipilimumab plus vaccine arm, and 1.5% (95% CI: 0.2%, 5.2%) in the vaccine arm.

Safety data were evaluated in 511 patients who received ipilimumab alone or in combination with the tumor vaccine. The most common (>5%) adverse reactions (AEs) were manifestations of ipilimumab's immunological mechanism of action leading to T-cell activation and proliferation. Such immune-mediated adverse reactions included diarrhea, pruritus, rash, and colitis. The most serious AEs were also immune-mediated adverse reactions. Ipilimumab was discontinued for adverse reactions in 10% of patients. Thirteen percent of ipilimumab treated patients experienced a high grade immune-mediated AE. The most common of these involved the colon, liver, skin, endocrine system, and nervous system. Management of immune-mediated AEs may include discontinuation of ipilimumab and initiation of high does corticosteroids.

The recommended does and schedule for ipilimumab is 3 mg/kg as an intravenous infusion every 3 weeks for a total of four doses.

Full prescribing information, including clinical trial information, safety, dosing, drug-drug interactions and contraindications is available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/125377s0000lbl.pdf.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA's MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

Rituximab

The following is a message from the FDA's Office of Oncology Drug Products Director, Dr. Richard Pazdur:

On January 28, 2011, the U.S. Food and Drug Administration approved rituximab (Rituxan®, Genentech, Inc) for maintenance therapy for patients with previously untreated follicular, CD-20 positive, B-cell non-Hodgkin lymphoma who achieve a response to rituximab in combination with chemotherapy.

The approval was based on the PRIMA study, an open-label, multinational, randomized Phase 3 study evaluating the benefit of rituximab maintenance therapy.  Patients with previously untreated follicular lymphoma with high tumor burden were randomized to receive either rituximab maintenance therapy or no maintenance therapy after achieving a response to a chemotherapy regimen including rituximab.

After achieving a complete or partial response to a rituximab-chemotherapy induction regimen, 1018 patients were randomized (1:1) to receive either rituximab 375 mg/m2 , intravenously, every 8 weeks (maximum 12 doses) or observation.  Forty percent of patients were > 60 years, 70% had stage IV disease, 96% had ECOG PS 0-1 and 42% had FLIPI (follicular lymphoma international prognostic index) scores of 3-5.  Induction therapy consisted of R-CHOP in 75% of patients, R-CVP in 22%, and R-FCM in 3%.

Progression-free survival, evaluated by an independent review committee, was the trial’s primary endpoint.  Maintenance rituximab reduced the risk of a PFS event by 46% (stratified HR: 0.54, 95% CI: 0.42, 0.70, stratified log-rank test p <0.0001).  Results for OS remain immature at this time

Safety data collection was limited to grade ≥ 2 infections, and grade ≥ 3 adverse reactions.  In 501 patients who received at least one dose of rituximab maintenance therapy, infections were reported more frequently compared to the observation arm (37 vs. 22%).  Grade 3-4 adverse reactions occurring at a higher incidence (≥ 2%) in the rituximab group were infections (4 vs. 1%) and neutropenia (4 vs. <1%).

Full prescribing information, including clinical trial information, safety, dosing, drug-drug interactions and contraindications is available at: 

http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/103705s5332lbl.pdf

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

On March 29, 2011, the U. S. Food and Drug Administration approved peginterferon alfa-2b (Sylatron™, Schering Corporation, Kenilworth, NJ 07033), for the treatment of patients with melanoma with microscopic or gross nodal involvement within 84 days of definitive surgical resection including complete lymphadenectomy.

The approval was based on a single trial, EORTC 18991, an open label, multi-center trial enrolling 1256 patients.  Patients who had been adequately surgically resected for their primary cutaneous melanoma and affected regional lymph nodes were randomized (1:1) to receive either Sylatron or observation for a 5 year period. Stratification factors included type of nodal involvement (microscopic versus gross), number of positive nodes (1, 2-4, 5 or more, or not assessed), Breslow primary thickness (less than 1.5 mm, ≥ 1.5 to 4 mm, ≥ 4 mm), ulceration of primary tumor (present or absent or unknown), sex, and study center.  Patients were assessed for local and regional recurrence or distant metastases every three months for the first two years of treatment and subsequently every six months through the end of the trial.  An independent review committee, blinded to randomization assignment and to information that would break the treatment blind, reviewed the case report form data to determine the occurrence, and the date of loco-regional recurrence, or distant metastasis.

The primary efficacy endpoint, relapse-free survival (RFS), was defined as the time to the earliest of local or regional recurrence, distant metastases, or death. Based on 696 RFS events, an improvement in RFS for Sylatron-treated patients [hazard ratio 0.82 (95% CI: 0.71, 0.96); unstratified log-rank p = 0.011] was observed.  The estimated median RFS was 34.8 months (95% CI: 26.1, 47.4) and 25.5 months (95% CI: 19.6, 30.8) in the Sylatron and observation arms, respectively.  Following 525 deaths on study, there was no difference in overall survival between the Sylatron and the observation arms
[hazard ratio 0.98 (95% CI: 0.82, 1.16)].

Safety was evaluated in 608 Sylatron-treated patients in EORTC 18991.  The most common (>60%) grade 1-4 adverse reactions experienced by Sylatron-treated patients were fatigue, increased ALT, increased AST, pyrexia, headache, anorexia, myalgia, nausea, chills, and injection site reactions.  The most common serious adverse reactions occurring in Sylatron-treated patients were fatigue, increased ALT, increased AST, and pyrexia.

Thirty-three percent of patients receiving Sylatron discontinued treatment due to adverse reactions.  The most common adverse reactions present at the time of treatment discontinuation were fatigue, depression, anorexia, increased ALT, increased AST, myalgia, nausea, headache, and pyrexia.  Five deaths were reported within 30 days of the last Sylatron dose.  Two were attributed to recurrent disease, two to cardiovascular disease possibly related to Sylatron, and one to an accident.

The recommended dose and schedule for Sylatron is 6 mcg/kg/week, subcutaneously for 8 doses, followed by 3 mcg/kg/week subcutaneously.  The maximum treatment period is 5 years (260 weeks).

Full prescribing information, including clinical trial information, safety, dosing, drug-drug interactions and contraindications is available at:  http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/103949s5153lbl.pdf

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).