ADCETRIS® (brentuximab vedotin) NEW INDICATION

• FLASCO
• September 15, 2015
• Drugs, News

ADCETRIS® (brentuximab vedotin)  NEW INDICATION

Dear Healthcare Professional:

Seattle Genetics is pleased to announce FDA approval for use of ADCETRIS® (brentuximab vedotin) as post-autologous hematopoietic stem cell transplantation (auto-HSCT) consolidation treatment for patients with classical Hodgkin lymphoma (HL) at high risk of relapse or progression. The FDA decision was based on the positive results from a phase 3 clinical trial called AETHERA, data from which were published in The Lancet in March 2015.

ADCETRIS is the Only Therapy Approved for Post-Auto-HSCT Consolidation Treatment for Patients with Classical HL at High Risk of Relapse or Progression

Based on the AETHERA trial results, ADCETRIS was also added to the National Comprehensive Cancer Network (NCCN) guidelines for up to one year of treatment in classical HL patients following auto-HSCT who had primary refractory disease or who had relapsed less than 12 months following frontline therapy.

ADCETRIS Demonstrated a Statistically Significant Increase in Progression-Free Survival vs. Placebo in the AETHERA Study

The Phase 3 AETHERA trial was a randomized, double-blinded, placebo-controlled study designed to evaluate the potential of single agent ADCETRIS to extend PFS post-auto-HSCT in patients with HL who have at least one risk factor for progression or relapse, as defined by at least 1 of the following risk factors including refractory disease, relapse < 12 months after frontline therapy, relapse > 12 months with extranodal disease. A total of 329 HL patients at risk of relapse or progression were enrolled, including 165 on the ADCETRIS arm and 164 on the placebo arm.

The trial achieved its primary endpoint and demonstrated a significant increase in PFS per independent review facility, with a hazard ratio of 0.57 (95% CI: 0.40, 0.81) and a p-value of 0.001. Median PFS was 43 months (95% CI: 30.4, 42.9) for patients who received ADCETRIS versus 24 months (95% CI: 11.5, not estimable) for patients who received placebo.

Overall survival (OS) data are immature, and no statistically significant difference in OS has been observed between the treatment arms. A further analysis of OS is planned in 2016.

ADCETRIS-treated patients received a median of 15 (range, 1 to 16) treatment cycles, indicating generally acceptable tolerability and a manageable adverse reaction profile. Patients in the placebo arm also received a median of 15 treatment cycles (range, 1 to 16). Adverse reactions that led to dose delays in more than 5 percent of ADCETRIS-treated patients were neutropenia (22 percent), peripheral sensory neuropathy (16 percent), upper respiratory tract infection (6 percent), and peripheral motor neuropathy (6 percent). Adverse reactions led to treatment discontinuation in 32 percent of ADECTRIS-treated patients; those that led to discontinuation in 2 or more patients were peripheral sensory neuropathy (14 percent), peripheral motor neuropathy (7 percent), acute respiratory distress syndrome (1 percent), paraesthesia (1 percent), and vomiting (1 percent).

The most common adverse events (≥20 percent), of any grade and regardless of causality, in the ADCETRIS arm were neutropenia (78 percent), peripheral sensory neuropathy (56 percent), thrombocytopenia (41 percent), anemia (27 percent), upper respiratory tract infection (26 percent), fatigue (24 percent), peripheral motor neuropathy (23 percent), nausea (22 percent), cough (21 percent) and diarrhea (20 percent). The most common adverse events (≥20 percent), of any grade and regardless of causality, in the placebo arm were neutropenia (34 percent), upper respiratory tract infection (23 percent), and thrombocytopenia (20 percent). Sixty-seven percent of patients on the ADCETRIS arm experienced peripheral neuropathy. Of those patients, 85 percent had resolution (59 percent) or partial improvement (26 percent) in symptoms at the time of their last evaluation, with a median time to improvement of 23 weeks (range 0.1-138).

Important Safety Information

BOXED WARNING

Progressive multifocal leukoencephalopathy (PML): JC virus infection resulting in PML and death can occur in patients receiving ADCETRIS® (brentuximab vedotin).

Contraindication

ADCETRIS is contraindicated with concomitant bleomycin due to pulmonary toxicity (e.g., interstitial infiltration and/or inflammation).

Warnings and Precautions

• Peripheral neuropathy: ADCETRIS treatment causes a peripheral neuropathy that is predominantly sensory. Cases of peripheral motor neuropathy have also been reported. ADCETRIS-induced peripheral neuropathy is cumulative. Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain or weakness and institute dose modifications accordingly.
• Anaphylaxis and infusion reactions: Infusion-related reactions, including anaphylaxis, have occurred with ADCETRIS. Monitor patients during infusion. If an infusion-related reaction occurs, interrupt the infusion and institute appropriate medical management. If anaphylaxis occurs, immediately and permanently discontinue the infusion and administer appropriate medical therapy.
• Hematologic toxicities: Prolonged (≥1 week) severe neutropenia and Grade 3 or 4 thrombocytopenia or anemia can occur with ADCETRIS. Febrile neutropenia has been reported with ADCETRIS. Monitor complete blood counts prior to each dose of ADCETRIS and consider more frequent monitoring for patients with Grade 3 or 4 neutropenia. Monitor patients for fever. If Grade 3 or 4 neutropenia develops, consider dose delays, reductions, discontinuation, or G-CSF prophylaxis with subsequent doses.
• Serious infections and opportunistic infections: Infections such as pneumonia, bacteremia, and sepsis or septic shock (including fatal outcomes) have been reported in patients treated with ADCETRIS. Closely monitor patients during treatment for the emergence of possible bacterial, fungal or viral infections.
• Tumor lysis syndrome: Closely monitor patients with rapidly proliferating tumor and high tumor burden.
• Increased toxicity in the presence of severe renal impairment: The frequency of ≥Grade 3 adverse reactions and deaths was greater in patients with severe renal impairment compared to patients with normal renal function. Avoid the use of ADCETRIS in patients with severe renal impairment.
• Increased toxicity in the presence of moderate or severe hepatic impairment: The frequency of ≥Grade 3 adverse reactions and deaths was greater in patients with moderate or severe hepatic impairment compared to patients with normal hepatic function. Avoid the use of ADCETRIS in patients with moderate or severe hepatic impairment.
• Hepatotoxicity: Serious cases of hepatotoxicity, including fatal outcomes, have occurred with ADCETRIS. Cases were consistent with hepatocellular injury, including elevations of transaminases and/or bilirubin, and occurred after the first dose of ADCETRIS or rechallenge. Preexisting liver disease, elevated baseline liver enzymes, and concomitant medications may also increase the risk. Monitor liver enzymes and bilirubin. Patients experiencing new, worsening, or recurrent hepatotoxicity may require a delay, change in dose, or discontinuation of ADCETRIS.
• Progressive multifocal leukoencephalopathy (PML): JC virus infection resulting in PML and death has been reported in ADCETRIS-treated patients. First onset of symptoms occurred at various times from initiation of ADCETRIS therapy, with some cases occurring within 3 months of initial exposure. In addition to ADCETRIS therapy, other possible contributory factors include prior therapies and underlying disease that may cause immunosuppression. Consider the diagnosis of PML in any patient presenting with new-onset signs and symptoms of central nervous system abnormalities. Hold ADCETRIS if PML is suspected and discontinue ADCETRIS if PML is confirmed.
• Pulmonary Toxicity: Events of noninfectious pulmonary toxicity including pneumonitis, interstitial lung disease, and acute respiratory distress syndrome, some with fatal outcomes, have been reported. Monitor patients for signs and symptoms of pulmonary toxicity, including cough and dyspnea. In the event of new or worsening pulmonary symptoms, hold ADCETRIS dosing during evaluation and until symptomatic improvement.
• Serious dermatologic reactions: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), including fatal outcomes, have been reported with ADCETRIS. If SJS or TEN occurs, discontinue ADCETRIS and administer appropriate medical therapy.
• Embryo-fetal toxicity: Fetal harm can occur. Advise pregnant women of the potential hazard to the fetus.

Most Common Adverse Reactions:

ADCETRIS was studied in 329 patients with classical HL at high risk of relapse or progression post-auto-HSCT in a placebo-controlled randomized trial. The most common adverse reactions (≥20%) in the ADCETRIS-treatment arm (167 patients), regardless of causality, were neutropenia, peripheral sensory neuropathy, thrombocytopenia, anemia, upper respiratory tract infection, fatigue, peripheral motor neuropathy, nausea, cough, and diarrhea.

Drug Interactions:

Concomitant use of strong CYP3A4 inhibitors or inducers, or P-gp inhibitors, has the potential to affect the exposure to monomethyl auristatin E (MMAE).

Use in Specific Populations:

MMAE exposure and adverse reactions are increased in patients with moderate or severe hepatic impairment or severe renal impairment. Avoid use.

For additional Important Safety Information, including Boxed WARNING, please see the full Prescribing Information for ADCETRIS at http://www.seattlegenetics.com/pdf/adcetris_USPI.pdf.

If you would like more information, please click on the links below:

• ADCETRIS.com
• NCCN Guidelines for the treatment of HL
• Publication of AETHERA data in the Lancet
• Publication of Hematopoietic Cell Transplantation Treatment Guidelines in Biology of Blood and Marrow Transplantation Journal

For additional support, please refer to SeaGen Secure®, a comprehensive assistance program for patients who have been prescribed products from Seattle Genetics and for the healthcare providers caring for them. Visit www.seagensecure.com or call 855.4SEAGEN (855.473.2436).

Sincerely,

Your ADCETRIS Team