Axplora

Earlier this year, NICE, the United Kingdom’s National Institute for Health and Care Excellence has issued a new Technology Appraisal Guidance for brentuximab vedotin (Adcetris®, Takeda) in the treatment of patients with CD30-Positive Hodgkin Lymphoma. On June 14 , 2017 NICE released their technology appraisal guidance for brentuximab vedotin – an antibody–drug conjugate that allows for the selective targeting of CD30-expressing cancer cells.

The review committee considered the groups of patients with CD30‑positive Hodgkin lymphoma which reflected the marketing authorisation for brentuximab vedotin. These were:

  • Adults with relapsed or refractory disease after autologous stem cell transplant
  • Adults with increased risk of disease relapse or progression after autologous stem cell transplant
  • Adults with relapsed or refractory disease after at least 2 previous therapies when autologous stem cell transplant or multi-agent chemotherapy is not an option.

Looking at these patient poulations, NICE’s guidance confirmed that brentuximab vedotin is now recommended as an option for treating CD30‑positive Hodgkin lymphoma in adults, only if patients:

  • have relapsed or refractory disease after autologous stem cell transplant and
    the manufacturer (Takeda) provides brentuximab vedotin at the price agreed with NHS England in the commercial access agreement.

NICE also recommends brentuximab vedotin for use within the Cancer Drugs Fund as an option for treating CD30‑positive Hodgkin lymphoma in adults, only if patients:

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  • have relapsed or refractory disease after at least 2 previous therapies and they cannot have autologous stem cell transplant or multi-agent chemotherapy and the conditions of the managed access agreement are followed.

Both recommendations are not intended to affect treatment with brentuximab vedotin that was started in the NHS before this guidance was published.

Adults having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.

Brentuximab vedotin is an antibody–drug conjugate comprising an anti-CD30 monoclonal antibody attached by an enzyme-cleavable linker to a potent chemotherapeutic agent, monomethyl auristatin E (MMAE). The antibody–drug conjugate selectively targets and kills CD30-expressing cancer cells such as classical Hodgkin lymphoma and systemic anaplastic large-cell lymphoma. Early phase I and II clinical trials demonstrated favorable response rates and toxic effects, and promising progression-free survival rates.

NCT01100502 (Aethera Trial) (CLINICAL TRIAL / BRENTUXIMAB VEDOTIN / SGN-035 / ADCETRIS®)
Fig 1.0: The AETHERA Trial is a Phase III Study of Brentuximab Vedotin, also known as SGN-35, in Patients at High Risk of Residual Hodgkin Lymphoma Following Stem Cell Transplant. PFS follow-up (year 2) included continued monitoring with scans at 18 and 24 months and quarterly clinical assessments. Patients in this trial who experienced disease progression per investigator during the study were unblinded and could receive brentuximab vedotin as part of a separate trial.

Recommendation
For the treatment of patients with relapsed or refractory disease after autologous stem cell transplant, the recommendation was mostly based on retrospective, non-randomized evidence.

For patients with relapsed or refractory disease after at least 2 previous therapies and they cannot have autologous stem cell transplant or multi-agent chemotherapy population 2, the company’s submission consisted of a randomized controlled trial (AETHERA; NCT01100502). The appraisal committee considered this to be compromised to fit the data to the relevant high-risk group.

The committee based decisions, in part,  on the AETHERA trial (n=329), a double-blind, randomized, controlled, phase III trial comparing brentuximab vedotin with placebo. The trial collected data between April 2010 and September 2012 and included patients with Hodgkin lymphoma at risk of having residual disease after autologous stem cell transplant defined as those who have 1 risk factor.

The key results of the AETHERA trial were:

  • Median progression-free survival assessed by independent review (primary outcome): 42.9 months for brentuximab vedotin; 24.1 months for placebo (HR 0.57, 95% CI 0.40 to 0.81; p=0.001)
  • Median progression-free survival assessed by investigators: not reached for brentuximab vedotin; 15.8 months for placebo (HR 0.50, 95% CI 0.36 to 0.70)
  • Overall survival (without adjustment for treatment switching): median not reached for either treatment; HR 1.15 (95% CI 0.67 to 1.97).

This definition used by the review committee was broader than that on which brentuximab vedotin’s regulatory approval was based and the definition in the final NICE scope. To identify the high-risk group reflecting clinical practice in England, the company redefined high-risk patient criteria and identified a subgroup of patients which were accepted by committee (that is, people with a positive PET scan result before autologous stem cell transplant, plus at least 1 more risk factor).

Clinical routine
The appraisal committee heard from the clinical experts that it was not routine practice in England to refer people for transplant who are at increased risk of disease relapse or progression, but it accepted that this population could be clinically relevant in the future.

The appraisal committee agreed that the clinical evidence base for all patients populations was associated with uncertainty. They concluded that there are no clinically relevant subgroups for which there is evidence of differential effectiveness. For the patient population with confirmed relapsed or refractory disease after autologous stem cell transplant, the overall response rate by independent review (primary outcome) was 75%.

For patients with relapsed or refractory disease after at least 2 previous therapies and they cannot have autologous stem cell transplant or multi-agent chemotherapy, the median progression-free survival assessed by independent review (primary outcome) was 42.9 months for brentuximab vedotin and 24.1 months for placebo while for the last patient group the overall response rate (pooled data-set) investigator assessed was 50%. The overall response rates from C25007 and the UK observational dataset were 48% and 51% respectively.

The most common adverse events are nervous system disorders, including peripheral neuropathy, dizziness, and demyelinating polyneuropathy.

The recommended dose is 1.8 mg/kg administered by intravenous infusion over 30 minutes every 3 weeks.

Pricing arrangement
In England, the price of brentuximab vedotin is GB £ 2,500 for a 50‑mg vial (excluding VAT; British national formulary June 2017). The pricing arrangement considered by the review committee during guidance development was one in which Takeda had agreed a patient access scheme with the Department of Health.

This scheme would have provided a simple discount to the list price of brentuximab vedotin with the discount applied at the point of purchase or invoice. The Department of Health considered that this patient access scheme would not constitute an excessive administrative burden on the NHS.

The commercial access agreement between the company and NHS England incorporates this same simple discount applied at the point of purchase or invoice of all brentuximab vedotin but also includes additional and separate commercial arrangements that apply only to the population in the Cancer Drugs Fund. The financial terms of the agreement are commercial in confidence.

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