Brentuximab vedotin

In August 2011, the U.S. FDA granted accelerated approval to the biologics license application (BLA) submitted by Seattle Genetics for the use of brentuximab vedotin[2] in the treatment of relapsed HL and ALCL.[3] In March 2018, the FDA granted an expansion of use to include first-line treatment of stage III and IV HL in combination with chemotherapy.[4]

In October 2012, the European Medicines Agency (EMA) gave it conditional marketing authorization for relapsed or refractory HL and ALCL.[5]

In November 2017, the FDA approved brentuximab vedotin as a treatment for patients with cutaneous T-cell lymphoma (CTCL) who have received prior systemic therapy.[6] This approval is for patients with primary cutaneous anaplastic large cell lymphoma (pcALCL) and CD30-expressing mycosis fungoides (MF).[6]

Brentuximab vedotin[8] consists of the chimeric monoclonal antibody brentuximab (cAC10, which targets the cell-membrane protein CD30) linked with maleimide attachment groups, cathepsin cleavable linkers (valine-citrulline), and para-aminobenzylcarbamate spacers to three to five units of the antimitotic agent monomethyl auristatin E (MMAE, reflected by the 'vedotin' in the drug's name).[9] The peptide-based linker bonds the antibody to the cytotoxic compound in a stable manner so the drug is not easily released from the antibody under physiologic conditions to help prevent toxicity to healthy cells and ensure dosage efficiency. The peptide antibody-drug bond facilitates rapid and efficient drug cleavage inside target tumor cell. The antibody cAC10 part of the drug binds to CD30 which often occurs on diseased cells but rarely on normal tissues. The antibody portion of the drug attaches to CD30 on the surface of malignant cells, delivering MMAE which is responsible for the anti-tumour activity.[10][11] Once bound, brentuximab vedotin is internalised by endocytosis and thus selectively taken up by targeted cells. The vesicle containing the drug is fused with lysosomes and lysosomal cysteine proteases, particularly cathepsin B, start to break down valine-citrulline linker and MMAE is no longer bound to the antibody and is released directly into the tumor environment. [12]

Skeletal formula of brentuximab vedotin. Three to five units of MMAE are attached to the monoclonal antibody (MAB) brentuximab via the spacer para-aminobenzylcarbamate (marked green), a cathepsin-cleavable linker (Cit=citrulline, Val=valine, marked blue), and an attachment group consisting of caproic acid and maleimide (marked brown).[11][13]

In a 2010 clinical trial,[14] 34% of patients with refractory Hodgkin Lymphoma achieved complete remission and another 40% had partial remission.[15] Tumor reductions were achieved in 94% of patients. In ALCL, 87% of patients had tumors shrink at least 50% and 97% of patients had some tumor shrinkage.[16]

Reports in 2013 showed interim results[17] from a Phase II, open-label, single-arm study designed to evaluate the antitumor activity of brentuximab vedotin in relapsed or refractory CD30-positive NHL, including B-cell neoplasms. These results demonstrated that single-agent brentuximab vedotin induced a 42% objective response rate and manageable safety profile among advanced diffuse large B-cell lymphoma patients.[18][19]

A phase III trial funded by Millennium Pharmaceuticals compared ABVD (a combination of the chemotherapy drugs doxorubicin, bleomycin, vinblastine, and dacarbazine) versus A+AVD (a combination of brentuximab vedotin plus AVD, or doxorubicin, vinblastine, and dacarbazine) for treatment of classical Hodgkin lymphoma and found substituting brentuximab vedotin for bleomycin has both improved efficacy and lowered toxicity.[20] A previously completed phase I study demonstrated that a greater number of patients experienced pulmonary toxicity with brentuximab vedotin-ABVD than with ABVD alone. Pulmonary fibrosis is a classical adverse effect of bleomycin; however, the incidence of pulmonary fibrosis in the brentuximab vedotin-ABVD arm was higher than the expected historical rate with ABVD alone.[21] Overall, 24 out of 25 patients treated with brentuximab vedotin and AVD achieved complete remission.[22]

Brentuximab vedotin is also being investigated as a substitute for vincristine (another mitotic inhibitor which prevents tubulin polymerization) in patients with being treated with CHOP (a combination of cyclophosphamide, hydroxydaunorubicin, vincristine, prednisone or prednisolone) for a non-Hodgkin lymphoma.

A phase III clinical trial is currently comparing the two combination therapies (CHOP and CHP-brentuximab vedotin) with estimated completion in December 2017.[23]

The ECHELON-1 phase 3 trial compared brentuximab vedotin with bleomycin both in combination with adriamycin, vinblastine, dacarbazine (AVD) chemotherapy as a firstline treatment for advanced classical Hodgkin lymphoma.[24]

Brentuximab vedotin was studied as monotherapy in 160 patients in two phase II trials. Across both trials, the most common adverse reactions (≥20%), regardless of causality, were chemotherapy-induced peripheral neuropathy (a progressive, enduring and often irreversible tingling numbness, intense pain, and hypersensitivity to cold, beginning in the hands and feet and sometimes involving the arms and legs), neutropenia (an immune system impairment), fatigue, nausea, anemia, upper respiratory tract infection, diarrhea, fever, rash, thrombocytopenia, cough and vomiting.[25]

Patients who are receiving strong CYP3A4 inhibitors concomitantly with brentuximab vedotin should be closely monitored for serious adverse events.[25]

Brentuximab vedotin is marketed as Adcetris.[27] Seattle Genetics and Millennium Pharmaceuticals/Takeda Oncology are jointly developing brentuximab vedotin. Under the terms of the collaboration agreement, Seattle Genetics has U.S. and Canadian commercialization rights and the Takeda Group has rights to commercialize in the rest of the world. Seattle Genetics and the Takeda Group are funding joint development costs for brentuximab vedotin on a 50:50 basis, except in Japan where the Takeda Group will be solely responsible for development costs.