Brentuximab Vedotin

Lymphomas are the most prevalent haematological malignancy in Australia. Amongst all malignancies, it is ranked the sixth most common form of cancer. Lymphomas are typically classified as Hodgkin’s lymphoma (HL) and non-Hodgkin lymphoma (NHL).

HL is a rare form of lymphoma and is characterised by the unique Reed-Sternberg cells.  It represents around 10% of all lymphomas and peaks during young adulthood. In 2010, there were 572 new cases of HL compared to 4462 cases of NHL reported in Australia. Australian statistics show that an average of 87% of adult patients are able to achieve five-year relative survival after receiving standard therapy, which includes multi-agent chemotherapy and autologous stem cell transplant (ASCT). Unfortunately, there is still no standard of care for patients who progress or relapse after second-line chemotherapy with or without post-ASCT.

The same issue is present with an aggressive form of peripheral T-cell NHL known as systemic anaplastic large cell lymphoma (sALCL). Patients that fail second-line treatment and also clinical trials do not have a specified standard of care to undergo. However, histological findings show that both Reed-Sternberg cells in HL and sALCL cells tend to express a characteristic surface antigen named CD30 which presents a unique drug-binding target.

Brentuximab vedotin, also known as SGN-35, is an antibody-drug conjugate (ADC) which targets tumor cells with the unique antigen CD30 and exerts its effect after internalisation into those cells. It is comprised of three components:

1. A chimeric immumoglobulin G1 (IgG1) antibody cAC10, specific for human CD30.
2. A potent anti-microtubule agent, monomethyl auristatin E (MMAE).
3. A protease-cleavable linker that covalently attaches MMAE to cAC10.

Brentuximab vedotin works by the binding of the ADC to CD30 on the tumour cells surface. This initiates the internalisation of brentuximab vedotin into the tumour cell, specifically the lysosome compartment. There, MMAE is released via proteolytic cleavage and then binds to tubulin resulting in the disruption of the microtubule network. This leads to G2/M phase cell cycle arrest and apoptotic death of the CD30-expressing tumour cell.

In December 2013, the Therapeutic Goods Administration (TGA) approved the use brentuximab vedotin (Adcetris^®), for two indications.

1. Treatment of adult patients with relapsed or refractory CD30+ HL:
   • Following ASCT; or
   • Following at least two prior therapies when ASCT or multi-agent chemotherapy is not a treatment option.
2. Treatment of adults with relapsed or refractory sALCL.

A multinational, open-label, phase II study was conducted in patients with CD30-positive relapsed or refractory HL after ASCT. Patients were treated with 1.8mg/kg of brentuxiamb vedotin IV every three weeks. Patients also remained on treatment for up to 16 cycles in the absence of disease progression or toxicity. The results were impressive and showed a high level of efficacy. Younes et al reported a 75% (95% CI: 64.9% to 82.6%) overall response rate with almost half of those patients achieving complete remission. Furthermore, the median progression free survival of this study was 5.6 months (95% CI: 5.0 to 9.0 months) versus 21.7 months for patients who achieved complete remission; about four times longer. The overall survival for this 24 months study was an impressive 22.4 months (95% CI: 21.7 to not estimable [NE]).

Similarly for sALCL, a multinational, open-label, phase II study was conducted in patients with CD30-positive relapsed or refractory sALCL after failing to respond to at least one prior therapy. They were also given 1.8mg/kg of brentuximab vedotin IV once every three weeks up to 16 doses. The outcome of the study was an overall response rate of 86% (95% CI: 74.6% to 93.9%) with a complete remission rate of 59% (95% CI: 43.2% to 69.8%). These outstanding results were supported by median progression free survival of 14.3 months (95% CI: 9.1 to NE).

The combination of brentuximab vedotin and bleomycin is contraindicated as it results in pulmonary toxicity. Hence, bleomycin is omitted in trials using brentuximab + ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) in HL. It is also contraindicated in patients with a diagnosis of progressive multifocal leukoencephalopathy (PML) or history of PML. MMAE is a substrate of CYP3A4/5 and p-glycoprotein (P-gp), co-administration with potent CYP inhibitors (e.g. grapefruit juice, ketoconazole) or inducers (e.g. rifampicin) and P-gp inhibitors (e.g. ketoconazole, verapamil) may affect its plasma concentration. Therefore, vigilant monitoring of brentuximab toxicity is required with concurrent use of the components above.

Brentuximab vedotin may cause a variety of side effects. Those that are clinically important are neutropenia (54-55%, severe 21%), peripheral neuropathy (52-53%, severe 8-10%), anaemia (33-52%), thrombocytopenia (16-28%, severe 10%), infusion-related reactions (12%) and PML (<1%). Other common side effects are nausea, fatigue, diarrhoea, pyrexia, vomiting, arthralgia, pruritus, myalgia, and alopecia. Neutropenia and peripheral neuropathy are the most common reasons for treatment delays or discontinuation. These may be managed with dose modification, and if required, growth factor support may be given for patients with persistent neutropenia. Observed incidents of peripheral neuropathy were predictable and consistent with other antimicrotubule drugs. There is usually no need for premedication prior to infusion. However, if a patient has experienced any prior infusion-related reactions, subsequent infusions should be pre-medicated with appropriate support therapy which may include paracetamol, an antihistamine and a corticosteroid.

The dosing for brentuximab vedotin is 1.8mg/kg with a maximum dose of 180mg (weight capped at 100kg). If dose reduction is required following severe side effects, a dose of 1.2mg/kg can be used instead. The manufacturer recommends the medicine to be infused via 150mL sodium chloride 0.9% over 30 minutes. It must not be administered as an intravenous push or bolus. Brentuximab vedotin should be given through a dedicated intravenous line and the solution must not be mixed with other medicines. Brentuximab should be refrigerated at 2-8°C (not frozen) and protected from light.

After its initial promising results, the next step is to determine the safety and efficacy of brentuximab vedotin in combination with mainstream chemotherapy. A German study combined brentixumab vedotin with DHAP (cisplatin, high-dose cytarabine and dexamethasone) and achieved an acceptable toxicity and efficacy profile. There are currently many ongoing phase I or II studies that are investigating the efficacy of combining brentuximab with other agents such as ipilimumab, rituximab and lenalidomide.

Brentuximab vedotin has played a vital part in providing treatment options and hope to patients with relapsed or refractory HL and sALCL. Fortunately, the medicine is now listed on the Pharmaceutical Benefit Scheme (PBS) which would save patients an estimated $20,000.00 per treatment cycle.