Green Light for Cancer Immunotherapies in Europe

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.

Targeting BTK with Ibrutinib in Relapsed or Refractory Mantle-Cell Lymphoma.


Bruton’s tyrosine kinase (BTK) is a mediator of the B-cell–receptor signaling pathway implicated in the pathogenesis of B-cell cancers. In a phase 1 study, ibrutinib, a BTK inhibitor, showed antitumor activity in several types of non-Hodgkin’s lymphoma, including mantle-cell lymphoma.


In this phase 2 study, we investigated oral ibrutinib, at a daily dose of 560 mg, in 111 patients with relapsed or refractory mantle-cell lymphoma. Patients were enrolled into two groups: those who had previously received at least 2 cycles of bortezomib therapy and those who had received less than 2 complete cycles of bortezomib or had received no prior bortezomib therapy. The primary end point was the overall response rate. Secondary end points were duration of response, progression-free survival, overall survival, and safety.


The median age was 68 years, and 86% of patients had intermediate-risk or high-risk mantle-cell lymphoma according to clinical prognostic factors. Patients had received a median of three prior therapies. The most common treatment-related adverse events were mild or moderate diarrhea, fatigue, and nausea. Grade 3 or higher hematologic events were infrequent and included neutropenia (in 16% of patients), thrombocytopenia (in 11%), and anemia (in 10%). A response rate of 68% (75 patients) was observed, with a complete response rate of 21% and a partial response rate of 47%; prior treatment with bortezomib had no effect on the response rate. With an estimated median follow-up of 15.3 months, the estimated median response duration was 17.5 months (95% confidence interval [CI], 15.8 to not reached), the estimated median progression-free survival was 13.9 months (95% CI, 7.0 to not reached), and the median overall survival was not reached. The estimated rate of overall survival was 58% at 18 months.


Ibrutinib shows durable single-agent efficacy in relapsed or refractory mantle-cell lymphoma.

Source: NEJM


Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial.

Rituximab plus chemotherapy, most often CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), is the first-line standard of care for patients with advanced indolent lymphoma, and for elderly patients with mantle-cell lymphoma. Bendamustine plus rituximab is effective for relapsed or refractory disease. We compared bendamustine plus rituximab with CHOP plus rituximab (R-CHOP) as first-line treatment for patients with indolent and mantle-cell lymphomas.
METHODS: We did a prospective, multicentre, randomised, open-label, non-inferiority trial at 81 centres in Germany between Sept 1, 2003, and Aug 31, 2008. Patients aged 18 years or older with a WHO performance status of 2 or less were eligible if they had newly diagnosed stage III or IV indolent or mantle-cell lymphoma. Patients were stratified by histological lymphoma subtype, then randomly assigned according to a prespecified randomisation list to receive either intravenous bendamustine (90 mg/m(2) on days 1 and 2 of a 4-week cycle) or CHOP (cycles every 3 weeks of cyclophosphamide 750 mg/m(2), doxorubicin 50 mg/m(2), and vincristine 1.4 mg/m(2) on day 1, and prednisone 100 mg/day for 5 days) for a maximum of six cycles. Patients in both groups received rituximab 375 mg/m(2) on day 1 of each cycle. Patients and treating physicians were not masked to treatment allocation. The primary endpoint was progression-free survival, with a non-inferiority margin of 10%. Analysis was per protocol. This study is registered with, number NCT00991211, and the Federal Institute for Drugs and Medical Devices of Germany, BfArM 4021335.
FINDINGS: 274 patients were assigned to bendamustine plus rituximab (261 assessed) and 275 to R-CHOP (253 assessed). At median follow-up of 45 months (IQR 25-57), median progression-free survival was significantly longer in the bendamustine plus rituximab group than in the R-CHOP group (69.5 months [26.1 to not yet reached] vs 31.2 months [15.2-65.7]; hazard ratio 0.58, 95% CI 0.44-0.74; p<0.0001). Bendamustine plus rituximab was better tolerated than R-CHOP, with lower rates of alopecia (0 patients vs 245 (100%) of 245 patients who recieved >/=3 cycles; p<0.0001), haematological toxicity (77 [30%] vs 173 [68%]; p<0.0001), infections (96 [37%] vs 127 [50%]); p=0.0025), peripheral neuropathy (18 [7%] vs 73 [29%]; p<0.0001), and stomatitis (16 [6%] vs 47 [19%]; p<0.0001). Erythematous skin reactions were more common in patients in the bendamustine plus rituximab group than in those in the R-CHOP group (42 [16%] vs 23 [9%]; p=0.024).
INTERPRETATION: In patients with previously untreated indolent lymphoma, bendamustine plus rituximab can be considered as a preferred first-line treatment approach to R-CHOP because of increased progression-free survival and fewer toxic effects.

Source: Lancet.

Radioimmunotherapy Consolidation for Mantle Cell Lymphoma.

A high response rate was achieved with limited cycles of R-CHOP followed by a single dose of 90Yibritumomab tiuxetan.

High overall and complete response rates can be achieved with six to eight cycles of R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) in patients with mantle cell lymphoma (MCL), but median response duration is only 18 to 24 months.

Given the high activity of radioimmunotherapy (RIT) in patients with relapsed MCL (J Clin Oncol 2009; 27:5213), investigators conducted a multicenter phase II trial to test the efficacy and safety of four cycles of R-CHOP plus yttrium-90 (90Y)–ibritumomab tiuxetan RIT consolidation in patients with previously untreated MCL.

Of 56 treatment-naive adults (median age, 60; 73% men; 91% with stage III–IV disease; 48% with extranodal involvement), 52 received four cycles of R-CHOP followed by a single dose of standard 90Y-RIT. The overall response rate was 82%, and response improved to complete or partial remission in 22 patients after 90Y-RIT. At a median follow-up of 72 months, the median time to treatment failure was 34.2 months; median overall survival (OS) had not been reached. The estimated 5-year OS rate trended higher for patients aged 65 versus those >65 (79% vs. 62%; P=0.08). Toxicities were as expected with R-CHOP and were primarily transient neutropenia and thrombocytopenia for 90Y-RIT.

Comment: Given the typically short duration of progression-free survival after immunochemotherapy in MCL patients, postinduction strategies are under study to improve outcomes. In younger patients, high-dose chemotherapy and autologous stem-cell transplantation are often utilized, whereas older or infirm patients might benefit from maintenance rituximab (JW Oncol Hematol Aug 21 2012). The present study confirms 90Y-RIT as an active agent that increases response rate and duration following abbreviated induction cycles, although without an established survival benefit as yet. Confirmatory studies will be important, as will optimizing patient selection for 90Y-RIT versus alternative postinduction regimens.

Source: Journal Watch Oncology and Hematology