European Commission grants authorization to Unituxin for pediatric neuroblastoma

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The European Commission granted a marketing authorization for Unituxin (dinutuximab) for the treatment of high-risk neuroblastoma in patients aged 12 months to 17 years, who have previously received induction chemotherapy and achieved at least a partial response, followed by myeloablative therapy and autologous stem cell transplantation.

Unituxin is administered in combination with granulocyte-macrophage colony-stimulating factor, interleukin-2, and isotretinoin.

The European approval was based on demonstration of improved event-free survival and overall survival in a multicenter, open-label, randomized trial (ANBL0032) sponsored by NCI under a Cooperative Research and Development Agreement with the drug’s sponsor, United Therapeutics Corp., and conducted by the Children’s Oncology Group.

The trial randomized (1:1) 226 patients to either the Unituxin/13-cis-retinoic acid arm or to RA alone. Patients in each arm received six cycles of treatment.

The Unituxin/RA arm consisted of Unituxin in combination with GM-CSF and RA (cycles 1, 3, and 5), Unituxin in combination with IL-2 and RA (cycles 2 and 4), and RA (cycle 6). Patients were 11 months to 15 years of age, with a median age 3.8 years.

The major efficacy outcome measure was investigator-assessed EFS, defined as the time from randomization to the first occurrence of relapse, progressive disease, secondary malignancy or death.

The primary intent-to-treat analysis found an improvement in EFS associated with Unituxin immunotherapy plus isotretinoin as compared to isotretinoin alone. The two-year estimates of EFS were 66 percent among subjects receiving Unituxin immunotherapy plus isotretinoin as compared with 48 percent in subjects receiving isotretinoin alone (log-rank test p = 0.033), although this difference did not reach formal statistical significance according to the pre-specified plan for interim analyses.

In addition, OS was evaluated with three years of follow-up after the EFS analysis as a secondary endpoint with a significant improvement observed among ITT subjects randomly allocated to receive Unituxin immunotherapy plus isotretinoin as compared with isotretinoin alone. The three-year estimates of OS were 80 percent compared with 67 percent among subjects receiving Unituxin immunotherapy plus isotretinoin and isotretinoin alone, respectively (log-rank test p = 0.0165).

Long-term overall survival was evaluated with five years of follow up after the EFS analysis and continued to demonstrate a survival advantage for patients who received Unituxin immunotherapy compared to those who received isotretinoin alone. The five-year estimates of OS were 74 percent for Unituxin immunotherapy compared to 57 percent for isotretinoin alone (log-rank test p = 0.030).

The most frequently occurring adverse reactions reported during the neuroblastoma studies were hypotension, pain, hypersensitivity, pyrexia, urticaria, capillary leak syndrome, anemia, hypokalemia, decreased platelet count, hyponatremia, increased alanine aminotransferase, decreased lymphocyte count and decreased neutrophil count. Additional adverse reactions characteristic of an allergic response were also reported, including anaphylactic reaction and bronchospasm.

Unituxin is a monoclonal chimeric antibody composed of murine variable heavy and light chain regions and the human constant region for the heavy chain kappa, and reacts specifically with the ganglioside GD2, which is highly expressed on the surface of the neuroblastoma cells and minimally expressed on the surface of normal human neurons, peripheral pain fibres, and skin melanocytes.

In March, Unituxin, in combination with GM-CSF, IL-2 and RA, became the first therapy to be approved by FDA for the treatment of pediatric patients with high-risk neuroblastoma who achieve at least a partial response to prior first-line multi-agent multimodality therapy.

Unituxin carries a Boxed Warning alerting patients and health care professionals that Unituxin irritates nerve cells, causing severe pain that requires treatment with intravenous narcotics and can also cause nerve damage and life-threatening infusion reactions, including upper airway swelling, difficulty breathing, and low blood pressure, during or shortly following completion of the infusion. Unituxin may also cause other serious side effects including infections, eye problems, electrolyte abnormalities and bone marrow suppression.