The European Medicines Agency (EMA) has recommended granting marketing authorization for three cancer immunotherapies ― pembrolizumab (Keytruda, Merck & Co, Inc) for melanoma, nivolumab (Opdivo, Bristol-Myers Squibb Company) for lung cancer, and dinutuximab (Unituxin, United Therapeutics Corporation) for neuroblastoma.
In addition, the EMA recommended approval for the additional indication of Waldenstrӧm’s macroglobulinaemia for ibrutinib (Imbruvica, Pharmacyclics, Inc, Janssen Biotech, Inc) and also for a generic version of bortezomib (Bortezomib Accord, Accord Healthcare) for use in the treatment of multiple myeloma and mantle cell lymphoma.
Pembrolizumab for Advanced Melanoma
Pembrolizumab will be the second drug that acts as a programmed death inhibitor for the treatment of advanced melanoma in Europe, joining nivolumab, which was recommended for approval for this indication just a few weeks ago. Both drugs are already approved in the United States for use in advanced melanoma.
The data supporting the recommendation for approval come from one uncontrolled study and early results from two ongoing randomized, controlled trials, one comparing pembrolizumab with standard chemotherapy, and the other comparing pembrolizumab with ipilimumab (Yervoy, Bristol-Myers Squibb Company), another immunotherapy but with a slightly different mechanism of action.
The Committee for Medicinal Products for Human Use (CHMP) says the data so far have demonstrated the efficacy of pembrolizumab in adults with unresectable or metastatic melanoma, both in patients who had and in those who had not previously received ipilimumab. The committee also looked at safety information from more than 1000 patients enrolled in clinical studies and regarded the safety profile to be manageable.
Nivolumab for Lung Cancer
Nivolumb was recommended for approval for use in the treatment of squamous non–small cell lung cancer (NSCLC) when the disease is advanced and the patient has already been treated with chemotherapy. It is the first immunotherapy to be approved for use in lung cancer, and was welcomed by experts when this approval was announced in the United States.
In Europe, for this indication the product will have the trade name Nivolumab BMS, whereas for the treatment of melanoma, it will be marketed as Opvido, the tradename used in other countries.
The CHMP notes that this recommendation for approval is based on data from a phase 3 trial in 272 patients with squamous NSCLC in whom chemotherapy had failed. These patients were randomly assigned to receive either nivolumab or chemotherapy with docetaxel. This study found that nivolumab improved overall survival compared with docetaxel (median, 9.2 months, compared with 6.0 months). After 12 months, 42% of patients treated with nivolumab were still alive compared with 24% of patients treated with docetaxel, the CHMP notes. Details of this study are due to be presented next week at the annual meeting American Society of Clinical Oncology.
There were also further data from an uncontrolled study involving 117 patients with squamous NSCLC who had undergone at least two previous chemotherapy treatments and who were then treated with nivolumab, the CHMP noted.
Dinutuximab for Neuroblastoma
Dinutuximab was recommended for approval for use in the treatment of high-risk neuroblastoma in children who had already responded to an induction treatment with chemotherapy, followed by myeloablative therapy and autologous stem-cell transplant. The product should be administered in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2 (IL-2), and isotretinoin.
The product was recently approved in the United States.
Neuroblastoma is a rare cancer, so dinutuximab has orphan drug designation for this indication. The tumor forms from immature nerve cells and is usually seen as a lump in the abdomen or around the spine. It typically occurs in children younger than 5 years, the EMA explained in a press release. In many cases, it is present at birth, but the diagnosis is made only later, when the cancer has already spread to other parts of the body, and the child begins to show symptoms of the disease.
Dinutuximab is a monoclonal antibody designed to recognize and attach to disialoganglioside (GD2), an antigen that is present in high amounts on the surface of neuroblastoma cells but in lower amounts in normal cells. When the product attaches to the neuroblastoma cells, it marks them as targets for the body’s immune system, which is then expected to attack the cancer cells and thereby reverse or slow down the progression of the disease, the EMA explained.
The recommendation for approval was based on data from a clinical trial in children with high-risk neuroblastoma who had already responded to chemotherapy (showing at least a partial response) and were further treated with myeloablative therapy and autologous stem-cell transplant. The study randomly assigned 230 patients to receive dinutuximab combined with GM-CSF and IL-2 and oral isotretinoin, or isotretinoin alone.
After 2 years, 66% of patients receiving the dinutuximab combination were alive and free from recurrence or tumor growth, compared with 48% of patients treated with isotretinoin alone.
Dinutuximab “provides a much-needed treatment option to prolong survival” of patients who are considered to have high-risk neuroblastoma, the agency commented.
The most common side effects of dinutuximab are pain, allergic reactions, and hypotension. Because the protein targeted by the product is also present on normal nerve cells, its use may cause irritation and severe pain of the nerve cells, so pain relief is recommended both before and during treatment. Despite prophylaxis, two thirds of children experience pain, and about 40% experience severe pain.
The CHMP recommended that the safety profile be further assessed post authorization, and the agency required the company to include this in their risk management plan for dinutuximab.
Ibrutinib for Rare Lymphoma
An indication extension was recommended for ibutinib (Imbruvica, Pharmacyclics, Inc, Janssen Biotech, Inc). This drug is already approved for use in chronic lymphocytic leukemia and mantle cell lymphoma. The new indication covers its use in Waldenstrӧm’s macroglobulinemia (also known as lymphoplasmacytic lymphoma), a type of non-Hodgkin’s lymphoma. Ibrutinib will be the first drug for the treatment of this rare blood cancer. It has orphan drug designation for this indication.
Waldenstrӧm’s macroglobulinemia is characterized by an excess of abnormal B lymphocytes and plasma cells in the bone marrow and sometimes in other organs, the EMA explains. These abnormal cells produce large amounts of an immunoglobulin M (IgM), which can make the blood thicker than normal. This cancer usually begins in people older than 60 years. Five years after diagnosis, between 36% and 87% of patients are still alive, depending on their individual risk factors.
Ibrutinib offers a novel strategy in the treatment of malignancies involving B lymphocytes. It acts as an inhibitor of Bruton’s tyrosine kinase (Btk), which has a key role in the survival of B lymphocytes and their migration to the organs where these cells normally divide. By blocking Btk, ibrutinib decreases survival and migration of B lymphocytes, thereby delaying the progression of the cancer, the agency explains.
The recommendation for approval is based on the results of a phase 2 study in 63 patients with previously treated Waldenstrӧm’s macroglobulinemia. Around 90% of the patients treated with ibrutinib responded positively to the treatment, and approximately 80% of patients were alive without disease progression after 18 months.
The adverse events reported during the clinical trial were similar to those observed in the already approved indications of ibrutinib, the agency noted. They include neutropenia and thrombocytopenia.
Generic Bortezomib for Multiple Myeloma
In addition, the EMA recommended for approval a generic version of bortezomib (Bortezomib Accord, Accord Healthcare) for the treatment of multiple myeloma and mantle cell lymphoma.
Bortezomib Accord is a generic version of Velcade (Takeda/Millennium), which has been authorized for use in the European Union since April 2004, the agency noted. “Studies have demonstrated the satisfactory quality,” it added, stating that because Bortezomib Accord is administered intravenously and is 100% bioavailable, a bioequivalence study vs the reference product Velcade was not required.