Abstract: The arrival of the CD30 directed antibody-drug conjugate, brentuximab vedotin (BV), has altered the approach to patients with classical Hodgkin lymphoma. Since initial approval in 2011, BV has been extensively studied in previously untreated and relapsed/refractory patients. Treatment indications for the antibody-drug conjugate have been expanded from the previously treated population to include maintenance therapy after autologous stem cell transplantation and recently, combination with chemotherapy in newly diagnosed advanced stage patients. This article will review the evolution of BV in classical Hodgkin lymphoma, detailing the studies that led to the approved indications and discussion of recent trials in combination with chemotherapy and immunotherapy.

Keywords: antibody-drug conjugate, brentuximab vedotin, CD30, immunotherapy, classical Hodgkin lymphoma, novel therapies

INTRODUCTION

Standard front-line regimens for classical Hodgkin lymphoma (cHL) have enabled durable remissions in 90% of early stage¹ and 75% of advanced stage patients.² Unfortunately, 10–30% will experience refractory or relapsed disease and only half of these patients are expected to achieve a long-term cure with high-dose chemotherapy followed by autologous stem cell transplantation (ASCT).³ As over 8000 new patients are diagnosed with cHL each year in the United States alone,⁴ there is a substantial need for more effective, novel therapies, particularly in the advanced stage and previously treated population.

The hallmark feature of cHL is the Reed-Sternberg (RS) cell, originated from B-cell lineage and characterized by high levels of CD30 expression. CD30 is a transmembrane glycoprotein of the TNF receptor superfamily that affects cell survival, proliferation, and apoptosis, and therefore is an ideal target for therapy in cHL.⁵ The antibody-drug conjugate brentuximab vedotin is comprised of a chimeric anti-CD30 IgG1 antibody linked to monomethyl auristatin E (MMAE), a microtubule-disrupting agent. Once bound to CD30, this complex is internalized, and lysosomal enzymes cleave the linker, releasing MMAE within the target cell and resulting in mitotic arrest and induction of apoptosis.⁶

BRENTUXIMAB VEDOTIN MONOTHERAPY

Initial efforts with CD30 directed monoclonal antibodies (mAb) were clinically unsuccessful. One early preclinical study indicated robust in vivo binding of CD30 expressing RS cells with the murine Ber-H2 mAb in 6 patients, but unfortunately there was no antitumor activity seen.⁷ Phase I and II studies of the chimeric anti-CD30 mAb, SGN-30, demonstrated tolerability, but lacked clinical activity.^8,9 The human anti-CD30 mAb, MDX-060, performed slightly better and was able to produce two complete responses (CR) and two partial responses (PR) amongst 63 relapsed/refractory patients, however, the median duration of response was only 2–5 months.¹⁰ From these studies, it was hypothesized that heavily pre-treated patients were unable to mount a sufficient antibody-dependent, cell-mediated immune response. Consequently, antibody-drug conjugation was considered as a mechanism to circumvent a dependence of drug efficacy on host immune reactivity. Ber-H2-saporin, an anti-CD30 mAb conjugated to a potent ribosome inhibitor (saporin), produced PRs in 4 of 4 cHL patients, but were of short duration (6–10 weeks).¹¹ Francisco et al had previously reported the feasibility of conjugating SGN-30 mAb to MMAE in a murine model. By demonstrating conjugate stability with both potent and selective cellular apoptosis,⁶ this ultimately led to the development of SGN-35 (Adcetris; Seattle Genetics Inc), more recently known as brentuximab vedotin (BV).

Initial phase I trials investigating BV in relapsed/refractory cHL demonstrated overall response rates (ORR) of 36–54% with CR of 21–29% in heavily pretreated patients.^12,13 The relative durability of response allowed for bridging to more definitive therapies including stem cell transplantation. These data led to the hallmark phase II trial evaluating the clinical efficacy of BV in 102 cHL patients with relapsed/refractory disease after autologous stem cell transplantation (ASCT).¹⁴ Patients were administered 1.8 mg/kg of BV every three weeks for up to 16 doses. Patients received a median of nine doses, achieving an overall response rate (ORR) of 75% and CR of 34%. The median time to objective response and CR was 5.7 weeks and 12 weeks, respectively. The median progression-free survival (PFS) was 9.3 months, and patients who achieved CR experienced a median duration of remission (DOR) of 20.5 months. With longer follow-up, the estimated 5-year PFS and overall survival (OS) was 22% and 41%, respectively, with 13 patients remaining in CR at five years.¹⁵ Peripheral neuropathy (PN) was the most common adverse event (55%), which improved or resolved in 80% of those affected after dose modification or discontinuation. Given these remarkable data, BV was approved by the FDA for patients with cHL who had progressive disease after ASCT or who had received at least two prior lines of therapy and were deemed inappropriate for ASCT (Table 1).