EC grants Marketing Authorisation for dinutuximab

The European Commission (EC) has granted Marketing Authorisation for United Therapeutics’ 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 (ASCT).

Dinutuximab is administered in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2 (IL-2), and isotretinoin.

Neuroblastoma is the most common extracranial solid cancer in childhood and the most common cancer in infancy, with an annual incidence in the European Union of approximately 1500 patients, of whom 50% are diagnosed as having high-risk disease.

The European approval was based on demonstration of improved event-free survival (EFS) and overall survival (OS) in a multicentre, open-label, randomised trial.

The trial randomised 226 patients to either the dinutuximab/13-cis-retinoic acid (isotretinoin) arm or the isotretinoin alone arm.  Patients in each arm received six cycles of treatment. The dinutuximab/ isotretinoin arm consisted of dinutuximab in combination with granulocyte macrophage-colony stimulating factor and isotretinoin (cycles 1, 3, and 5), dinutuximab in combination with interleukin-2 and isotretinoin (cycles 2 and 4), and isotretinoin (cycle 6). Patients were 11 months to 15 years of age.

A “significant improvement” in overall survival in patients receiving dinutuximab plus isotretinoin

The major efficacy outcome measure was investigator-assessed EFS, defined as the time from randomisation 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 dinutuximab immunotherapy plus isotretinoin as compared to isotretinoin alone. The two-year estimates of EFS were 66% among subjects receiving dinutuximab immunotherapy plus isotretinoin as compared with 48% in subjects receiving isotretinoin alone although this difference did not reach formal statistical significance according to the pre-specified plan for interim analyses. In addition, OS was evaluated with 3 years of follow-up after the EFS analysis as a secondary endpoint with a significant improvement observed among subjects randomly allocated to receive dinutuximab immunotherapy plus isotretinoin as compared with isotretinoin alone. The three-year estimates of OS were 80% compared with 67% among subjects receiving dinutuximab immunotherapy plus isotretinoin and isotretinoin alone, respectively. 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 dinutuximab immunotherapy compared to those who received isotretinoin alone. The five-year estimates of OS were 74% for dinutuximab immunotherapy compared to 57% for isotretinoin alone.