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Background
Lymphomas are cancers of the lymphatic system. Hodgkin's lymphoma (HL) and anaplastic large-cell lymphoma (ALCL, a rare type of non-Hodgkin lymphoma) are the two most common tumors expressing CD30. The National Cancer Institute estimates that about 9,000 new cases of HL will be diagnosed in the United States in 2011 and about 1,300 people will die from the disease. CD30 is abundantly and selectively expressed on the surface of Hodgkin Reed-Sternberg cells, ALCLs, and other lymphoid malignancies as well as on several non-lymphoid malignancies including selected germ cell tumors. Expression of CD30 on normal cells is highly restricted, thereby allowing differential targeting of malignant cells. CD30, a member of the tumor necrosis factor (TNF)-receptor family has pleiotropic biologic functions, and antibodies targeting CD30 and other TNF family receptors can exhibit both agonistic and antagonistic signaling functions (Alley et al, 2010; Deutsch et al, 2011; NCI, 2011).
Patients with relapsed or refractory HL and ALCL usually have a poor prognosis. Individuals with these histologies who subsequently progress after salvage chemotherapy and autologous stem cell transplantation (ASCT) have very limited treatment options and are in need of novel effective therapies. Recently, the antibody-drug conjugate (ADC) field has made significant progress as a consequence of careful optimization of several parameters, including mAb specificity, drug potency, linker technology, as well as the stoichiometry and placement of conjugated drugs. The underlying reason for this has been obtained in pre-clinical biodistribution and pharmacokinetics studies showing that targeted delivery leads to high intra-tumoral free drug concentrations, while non-target tissues are largely spared from chemotherapeutic exposure. Developments in the field have led to an increase in the number of ADCs being tested clinically. Recently, ADCs targeting CD30, such as brentuximab vedotin (cAC10-vcMMAE, SGN 35, SGN-35), have shown striking activity in phase I and II clinical studies, with manageable toxicity. This has defined an important emerging role for targeting of CD30 in the setting of HL, ALCL, and possibly other CD30+ malignancies. Brentuximab vedotin consists of 3 components: (i) the chimeric IgG antibody cAC10, specific for human CD30, (ii) the potent microtubule disruptive cytotoxic agent, mono-methyl auristatin E (MMAE), and (iii) a protease-cleavable linker that co-valently attaches MMAE to cAC10 (Ansell, 2011; Deutsch et al, 2011).
In a phase I, open-label, multi-center dose-escalation study, Younces et al (2010) administered brentuximab vedotin (at a dose of 0.1 to 3.6 mg/kg body weight) every 3 weeks to 45 patients with relapsed or refractory CD30-positive hematologic cancers, primarily HL and ALCL. Patients had received a median of 3 previous chemotherapy regimens (range of 1 to 7), and 73 % had undergone autologous stem-cell transplantation (ASCT). The maximum tolerated dose was 1.8 mg/kg, administered every 3 weeks. Objective responses, including 11 complete remissions, were observed in 17 patients. Of 12 patients who received the 1.8-mg/kg dose, 6 (50 %) had an objective response. The median duration of response was at least 9.7 months. Tumor regression was observed in 36 of 42 patients who could be evaluated (86 %). The most common adverse events were diarrhea, fatigue, nausea, neutropenia, pyrexia, and peripheral neuropathy. The authors concluded that brentuximab vedotin induced durable objective responses and resulted in tumor regression for most patients with relapsed or refractory CD30-positive lymphomas in this phase I study. Treatment was associated primarily with grade 1 or 2 (mild-to-moderate) toxic effects.
Foyil and Bartlett (2011) described the preliminary findings of brentuximab vedotin for the treatment of patients with CD30+ lymphomas in large phase II clinical trials -- response rates of 75 % in relapsed/refractory HL and 87 % in relapsed/refractory systemic ALCL were reported. Brentuximab vedotin is well-tolerated with manageable side effects including peripheral sensory neuropathy. This ADC is currently under investigation in numerous clinical trials, including in combination with front-line chemotherapy for high-risk HL and in a placebo-controlled, phase III trial for patients with HL at high risk for residual disease following ASCT. The impressive response rates and limited toxicity of brentuximab vedotin are very promising for relapsed/refractory patients with few treatment options. In addition, the possibilities for incorporation into front-line therapies for both HL and systemic ALCL are intriguing.
On August 19, 2011, the Food and Drug Administration (FDA), under its accelerated approval program where surrogate endpoints are acceptable, approved brentuximab vedotin (Adcetris) for the treatment of patients with HL whose disease has progressed after ASCT or after 2 prior chemotherapy treatments for those who are not candidates for ASCT. The FDA also approved brentuximab vedotin for the treatment of patients with ALCL whose disease has progressed after 1 prior chemotherapy treatment. Brentuximab vedotin is the first new FDA-approved drug for HL since 1977 and the first drug specifically indicated for the treatment of ALCL. The effectiveness of brentuximab vedotin in patients with HL was evaluated in a clinical study involving 102 patients. In the open-lavel, single-arm, multi-center trial, patients were only treated with brentuximab vedotin. The study’s primary endpoint was objective response rate, the percentage of patients who experienced complete or partial cancer shrinkage or disappearance following treatment. A total of 73 % of patients achieved either a complete or partial response to the treatment. On average, these patients responded to the therapy for 6.7 months. The effectiveness of brentuximab vedotin in patients with systemic ALCL was evaluated in a single clinical study involving 58 patients. In the phase II, open-label, single-arm, multi-center trial, patients were only treated with brentuximab vedotin. Similar to the HL trial, the trial’s primary endpoint was objective response rate. Of the patients receiving brentuximab vedotin for ALCL, 86 % experienced either a complete or partial response and responded on average for 12.6 months. The most common adverse reactions experienced with brentuximab vedotin were anemia, cough, diarrhea, fatigue, fever, nausea, neutropenia, peripheral sensory neuropathy, thrombocytopenia, upper respiratory infection, and vomiting.
Oki and Younes (2012) noted that brentuximab vedotin has been approved by the FDA for the treatment of relapsed or refractory HL and ALCL. The effectiveness of brentuximab vedotin in other CD30(+) lymphomas is currently being investigated. These investigators reviewed the currently available treatment options for systemic peripheral T-cell lymphomas (PTCL) and the role of brentuximab vedotin in relapsed or refractory ALCL. In addition, ongoing clinical trial of brentuximab vedotin in relapsed PTCL and combination therapy with other chemotherapies for initial treatment of CD30(+) lymphoma were also reviewed. The authors concluded that brentuximab vedotin has established its role in the treatment of relapsed or refractory HL and ALCL. In the next few years, the effectiveness of this agent in other CD30(+) lymphomas will be described. The safety and effectiveness of several brentuximab-based combination regimens, including use as front-line chemotherapy is under investigation.
The recommended dosage of brentuximab vedotin (Adcetris) is 1.8 mg/kg body weight administered only as an intravenous infusion over 30 minutes every 3 weeks. Treatment can be continued until a maximum of 16 cycles, disease progression or unacceptable toxicity.
On January 13, 2012, the FDA notified the public that 2 additional cases of progressive multifocal leukoencephalopathy (PML) have been reported with Adcetris (brentuximab vedotin). Due to the serious nature of PML, a new Boxed Warning high-lighting this risk has been added to the drug label. At the time of Adcetris' approval in August 2011, 1 case of PML was described in the Warnings and Precautions section of the label. In addition, a new Contraindication warning against use of Adcetris with bleomycin due to increased risk of pulmonary toxicity has been added to the drug label.
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