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Targeted therapies in CD30+ malignancies

The cell receptor CD30 belongs to the tumour necrosis super family and is expressed in a variety of haematological malignancies and some non-lymphoid malignancies, such as embryonal carcinoma. CD30 has pleiotropic biologic functions. In particular, Hodgkin lymphoma (HL) and anaplastic large cell lymphoma (ALCL) have high expression rates of CD30 whereas normal CD30 expression is restricted to a relatively small proportion of activated B cells, T cells, and eosinophils. Thus, CD30 represents an ideal target for monoclonal antibody therapy. 
Brentuximab vedotin
Brentuximab vedotin (Adcetris®) is an antibody–drug conjugate that comprises a human chimeric imunoglobulin G1 monoclonal antibody (SGN-30) directed against CD30 that is covalently linked, via a protease-cleavable dipeptide linker to a microtubule-disrupting agent, monomethyl auristatin E (MMAE). Responses to bretuximab vedotin might be related not only to the cytotoxic effect due to release of MMAE within the malignant cell but also to an apoptotic or proliferative response and to its effect on the tumour microenvironment.1,2 Because MMAE crosses the cell membrane and is released into the surrounding extracellular matrix, brentuximab vedotin also potentially exerts cytotoxic activity on ‘bystander’ tumour cells, irrespective of CD30 status.2
Therapeutic application of brentuximab vedotin
HL and relapsed or refractory disease
HL is one of the most curable types of cancer. Although systemic chemotherapy is highly effective even in advanced stage disease, approximately 15–30% of patients with HL fail to achieve long-term remission with first-line chemotherapy. The standard of care for these patients is salvage chemotherapy followed by autologous stem cell transplant (ASCT) in responding patients. However, for 20–30% of patients, ASCT is not an option and approximately 30–50% will experience another relapse after ASCT.
The introduction of brentuximab vedotin has greatly improved the outcome of patients with relapsed or refractory (r/r) HL. In the pivotal Phase II, multicentre trial of bretuximab vedotin monotherapy, a total of 102 patients with r/r HL were treated with brentuximab vedotin 1.8mg/kg by intravenous infusion every three weeks.3 In the absence of disease progression or prohibitive toxicity, patients received a maximum of 16 cycles. Overall, the study cohort had a poor prognosis because the median time to relapse after ASCT was only 6.7 months and 71% had not achieved a complete remission (CR) or had experienced relapse within three months of front-line therapy. Remarkably, 75% of patients achieved an objective response and 34% obtained a CR.3 The median duration of treatment was nine months and the most clinically meaningful adverse event was cumulative grade 1 or 2 peripheral neuropathy, which typically developed after prolonged exposure to the drug. However, it was largely reversible after treatment was completed or discontinued or the dose was reduced. Further adverse events reported by ≥ 10% included nausea, fatique, neutropenia, diarrhoea and pyrexia.
More recently, follow-up data of the pivotal study have become available.4 After a median observation period of approximately three years, median overall survival (OS) and progression-free survival (PFS) were estimated at 40.5 months and 9.3 months, respectively. Notably, 16 of the 34 patients (47%) who achieved CR on brentuximab vedotin remained progression-free after being followed a median of 53 months, and 12 of 16 patients remained progression-free without a consolidative allogeneic SCT. Younger age, less functional impairment, and lower disease burden at baseline were associated with CR and prognostic for longer survival. 
A similar response rate of 68% was reported by another prospective trial that included 37 patients with r/r HL after induction chemotherapy.5 Brentuximab vedotin was administered for a total of four cycles. Thirty-two patients (86%) were able to proceed to ASCT, with 24 patients (65%) being in CR at time of ASCT. 
An objective response rate of 60% (CR in 22%) with a median response duration of eight months was found in a retrospective study on 45 heavily pretreated patients with r/r HL.6  Furthermore, a large retrospective analysis of 240 patients who had relapsed after prior ASCT, or after two lines of chemotherapy and were enrolled in the French Named-Patient Program, reported an overall response rate of 60.5%.7 In this study, patients received a median of six cycles of brentuximab vedotin. With median follow-up at 16.1 months, median PFS was 6.8 months and this was significantly longer for patients who underwent allogeneic SCT after brentuximab vedotin (median PFS 18.8 months). The most common adverse events (≥10%) were anaemia (39%), peripheral neuropathy (29.3%), thrombocytopenia (28%), neutropenia (23%), diarrhoea (14%) and infections (10%).
Patients with HL who previously experienced a CR or PR with brentuximab vedotin discontinued treatment while in remission, and subsequently experienced disease progression or relapse may benefit from retreatment with brentuximab vedotin.8 This approach resulted in a 60% response rate (30% CR) with an estimated median duration of response for responding patients of 9.5 months. Notably, 45% of patients with CR had response durations of over one year. With the exception of a higher rate of peripheral motor neuropathy, retreatment with brentuximab vedotin was associated with similar side effects seen in the pivotal trials. 
Consolidation therapy after ASCT Brentuximab vedotin also proved effective in high-risk patients with HL who undergo an ASCT. Results from a placebo-controlled, randomised, Phase III trial evaluating the effect of brentuximab vedotin on PFS and OS in high-risk patients with HL in the post–ASCT setting have been published.9 Patients with unfavourable-risk r/r classic HL who had undergone ASCT were randomly assigned to receive 16 cycles of 1.8mg/kg brentuximab vedotin or placebo intravenously every three weeks, starting 30–45 days after transplantation. Eligible patients had at least one of the following risk factors for progression after ASCT: primary refractory HL (failure to achieve CR); relapsed HL with an initial remission duration of less than 12 months; or extranodal involvement at the start of pre-transplantation salvage chemotherapy. At a median follow-up of 30 months, the median PFS was 42.9 months for patients in the brentuximab vedotin group compared with 24.1 months for those in the placebo group (hazard ratio (HR) 0.57, p=0.0013). Delivery of brentuximab vedotin was generally well tolerated and the benefit of consolidation treatment was observed across most subgroups.
However, patients who were PET-negative pre-ASCT did not benefit from consolidation therapy although PET scans were not per-protocol mandated (69.3% of patients had a pre-ASCT PET scan).
The beneficial effects of brentuximab vedotin consolidation therapy were maintained during long-term follow-up.10 Approximately three years after the last patient was randomised, treatment-induced peripheral neuropathy had occurred in 112 of 167 (67%) patients receiving brentuximab vedotin, with the majority of these patients experiencing improvement (23% of patients) or complete resolution (65%) of neuropathy symptoms.
Based on these results, brentuximab vedotin is now approved not only for r/r HL but also for consolidation after ASCT. Current ESMO and NCCN guidelines recommend brentuximab vedotin as an option for patients with relapsed or refractory classical HL who have failed HDCT/ASCT or at least two prior chemotherapy regimens. 
Front-line therapy 
The encouraging results achieved with brentuximab vedotin in patients with r/r HL were the basis for clinical studies evaluating the combination of brentuximab vedotin and multi-agent chemotherapy in untreated, newly diagnosed patients with HL. In a small pilot study, brentuximab vedotin and AVD (adriamycin, vinbastine, dacarbazine) (BrAVD) followed by involved-site radiotherapy was well tolerated and proved effective in early stage, unfavourable risk HL.11 After four cycles of BrAVD, 27 of 30 patients were PET-negative, two patients proved refractory, and one patient, after a single treatment of BrAVD, developed hypertension (grade 3) and peripheral motor and sensory neuropathy (grade 3) and came off study. 
Phase III studies in the front-line setting comparing BrAVD with ABVD (NCT 01712490) or BrECADD (brentuximab, etoposide, adriamycin, dacarbazine, dexamethasone (BrECADD) with the escalated BEACOPP regimen (NCT02661503) are ongoing. 
Systemic ALCL is an aggressive CD30-positive subtype of peripheral T-cell lymphoma (PTCL) accounting for approximately 2–3% of all lymphoid malignancies. In the international peripheral T-cell and natural killer/T-cell lymphoma study, it is the third most frequent type of aggressive PTCL.12The translocation t(2;5)(p23;q35) can be found in approximately 50% of patients, resulting in the expression of the nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) fusion protein. The prognosis of patients with ALK-positive ALCL is markedly better than that of ALK-negative ALCL.13 A significant proportion of patients can be cured by using CHOP-like regimens. However, approximately 40% of patients with ALK-positive disease and over 60% of those with ALK-negative disease develop recurrent disease after front-line chemotherapy.13
Brentuximab vedotin is also a major advance in the treatment of r/r ALCL. In a multinational, open-label, Phase II study, that included 58 patients with r/r ALCL, treatment with brentuximab vedotin resulted in a 86% overall response (57% CR, 29% PR).14 Responses generally occurred within 6 weeks of treatment initiation and the median durations of overall response and CR were 12.6 and 13.2 months, respectively. Grade 3 or 4 adverse events that occurred in at least 10% of patients were neutropenia (21%), thrombocytopenia (14%), and peripheral sensory neuropathy (12%). Dose delays and dose reductions to 1.2mg/kg were used to manage adverse events, including events of peripheral neuropathy, and allow continued treatment in some patients. Notably, subsequent resolution or improvement of peripheral neuro-pathy was observed in 81% of patients.
The estimated five-year OS and PFS for all enrolled patients was 60% and 39%, respectively.15 After a median follow-up of 71.4 months the median PFS was 20 months and the median OS has not been reached. These results demonstrate that among patients with r/r systemic ALCL, the majority have achieved clinically significant durable remissions, and a subset may have been cured with single-agent brentuximab vedotin. Thus, CD30 targeting with bretuximab vedotin in r/r ALCL is a remarkable step forward. Brentuximab vedotin is approved for the treatment of r/r ALCL.
A randomised Phase III trial is ongoing to evaluate the combination of brentuximab vedotin with cyclophosphamide, doxorubicin, and prednisone for frontline treatment of CD30-expressing peripheral T-cell lymphomas, including systemic ALCL. 
Other CD30+ lymphoproliferative disorders
Brentuximab vedotin has also been used in cutaneous T-cell lymphomas (CTCL),16 diffuse large B-cell lymphoma,17 primary mediastinal B-cell lymphoma18 and other PTCL19 with varying success. Of note, the response rate to brentuximab vedotin was 73% in the CTCL study with a CR rate of 35%.16 A number of Phase III clinical trials continue to assess brentuximab vedotin for patients with haematologic malignancies but it has not yet been approved for treatment of these entities.
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