Based on positive data from the Phase III AETHERA trial (SGN35-005; NCT01100502) of brentuximab vedotin (Adcetris®; Seattle Genetics, Inc/Takeda Oncology) as consolidation therapy immediately following an autologous stem cell transplant or ASCT in Hodgkin lymphoma (HL) patients at high risk of relapse, Seattle Genetics submitted a supplemental Biologics License Application (BLA) to the U.S. Food and Drug Administration (FDA).
Lymphoma is a general term for a group of cancers that originate in the lymphatic system. There are two major categories of lymphoma: HL and non-Hodgkin lymphoma. HL is distinguished from other types of lymphoma by the presence of one characteristic type of cell, known as the Reed-Sternberg cell. The Reed-Sternberg cell generally expresses CD30.
According to the American Cancer Society, approximately 9,050 cases of HL will be diagnosed in the United States during 2015 and more than 1,150 will die from the disease. Globally, there are more than 62,000 cases of HL diagnosed each year. Although frontline combination chemotherapy can result in durable response rates, up to 30% of these patients relapse or are refractory to frontline treatment and have few therapeutic options beyond ASCT.
Brentuximab vedotin is an antibody-drug conjugate (ADC) directed to CD30, which is expressed in classical hodgkin lymphoma (HL) and systemic anaplastic large cell lymphoma (sALCL). CD30 (tumor necrosis factor receptor superfamily, member 8; TNFRSF8) is a type I transmembrane receptor which shares sequence homology in the extracellular domain with other members of the tumor necrosis factor (TNF) receptor superfamily.
CD30 is highly expressed on the Reed Sternberg cells, the large, often multinucleated cells with a peculiar morphology and an unusual immunophenotype, that does not resemble any normal cell in the body and which form the hallmark of Hodgkin’s disease (HD). On normal tissues, CD30 has a restricted expression profile limited to activated T cells, activated B cells, and activated natural killer cells. This expression profile makes CD30 an ideal target for monoclonal antibody (mAb)-based therapies of Hodgkin’s disease.
One such agent, brentuximab vedotin, links the chimeric anti-CD30 monoclonal (cAC10), derived from the fusion of the variable heavy and light region of the murine anti-CD30 antibody AC10 with the constant gamma1-heavy and kappa-light region of the human immunoglobulin, via a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E (MMAE), a synthetic derivative of dolastatin 10, a natural cytostatic pseudo peptide which was originally isolated from the marine shell-less mollusk Dorabella auricularia. The linker system, which consists of a thiolreactive maleimidocaproyl spacer, the dipeptide valine–citrulline linker, and a PABC spacer, is designed to be stable in the bloodstream but to release MMAE, which exerts its potent cytostatic effect by inhibiting microtubule assembly, tubulin-dependent GTP hydrolysis and polymerization, upon internalization into CD30-expressing tumor cells.
To date, the drug is approved in relapsed HL and sALCL but is currently not approved for consolidation therapy in HL patients immediately after ASCT.
“With approximately half of all Hodgkin lymphoma patients who undergo an autologous stem cell transplant experiencing disease relapse, there is a significant need to identify regimens that extend progression-free survival,” explained Clay B. Siegall, Ph.D., President and Chief Executive Officer of Seattle Genetics. “Results from the AETHERA trial demonstrated that treating high risk Hodgkin lymphoma patients with brentuximab vedotin in following autologous stem cell transplant resulted in a statistically significant improvement in progression-free survival with a manageable safety profile. We believe that this is clinically meaningful and supports a label expansion for brentuximab vedotin in this setting.”
The supplemental BLA is based on positive results from a phase III clinical trial called AETHERA, a randomized, double-blind, placebo-controlled, multicenter trial to evaluate the efficacy and safety of brentuximab vedotin and best supportive care compared to placebo and best supportive care in treatment of residual HL following ASCT, that were presented at the 56th American Society of Hematology (ASH) Annual Meeting held in San Francisco in December 2014.
The AETHERA trial in 329 HL patients at high risk of relapse achieved its primary endpoint and demonstrated a significant increase in progression-free survival (PFS) per independent review facility, with a hazard ratio of 0.57 and a p-value of 0.001. Median PFS was 43 months for patients who received brentuximab vedotin versus 24 months for patients who received placebo and best supportive care. The two-year PFS rate was 63% in the brentuximab vedotin arm compared to 51% in the placebo arm.
Furthermore, the PFS benefit was consistent across all pre-specified subgroups, including primary refractory patients, patients who relapsed within twelve months of frontline therapy and patients who relapsed after twelve months with extranodal disease.
The most common adverse events in the brentuximab vedotin arm were peripheral sensory neuropathy (56%), neutropenia (35%), upper respiratory tract infection (26%), fatigue (24%) and peripheral motor neuropathy (23%). The most common adverse events in the placebo arm were upper respiratory tract infection (23%), fatigue (18%), peripheral sensory neuropathy (16%), cough (16%) and neutropenia (12%). Eighty-five percent of patients with peripheral neuropathy on the brentuximab vedotin arm had resolution or improvement in symptoms with a median time to improvement of 23.4 weeks.
Post marketing data
Submission of safety data from the AETHERA trial to the FDA is a post-marketing requirement that Seattle Genetics will fulfill with this submission of the supplemental BLA.
The current indications for brentuximab vedotin are approved under accelerated approval based on overall response rate. An improvement in patient-reported outcomes or survival has not been established. Continued approval for these indications may be contingent upon verification and description of clinical benefit in confirmatory trials.