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News Briefs

OBTN, February 2008, Volume 2, Issue 2

1) Lenalidomide (Revlimid) has been granted orphan medicinal product designation by the European Commission (EC) for treatment

Lenalidomide Receives Orphan Medicinal Product Designation from the European Commission for Chronic Lymphocytic Leukemia

Chronic lymphocytic leukemia (CLL) is a hematological malignancy that affects approximately 165,000 people in the European Union (EU), based on an estimated prevalence rate of 3.5 per 10,000.

Lenalidomide (Revlimid) has been granted orphan medicinal product designation by the European Commission (EC) for treatment of chronic lymphocytic leukemia (CLL) following the favorable opinion of the European Medicines Agency’s (EMEA) Committee for Orphan Medicinal Products (COMP). Orphan medicinal product designation is granted by the EC to promote development of drugs to treat rare diseases or conditions.

Lenalidomide is an immunomodulatory agent that stimulates T-cells, inhibits the production of tumor necrosis factor alpha and vascular endothelial growth factor, and impairs the interaction between bone marrow stroma and hematopoietic cells.

Orphan designation will give lenalidomide access to the Centralized Procedure for the application for marketing approval, reduce fees associated with applying for marketing approval and protocol assistance, and provide 10 years of market exclusivity once approved for treatment of CLL.

Alessandra Ferrajoli, MD, Assistant Professor of Medicine, University of Texas MD Anderson Cancer, Houston, Texas, recently reported preliminary results of a study showing that lenalidomide, delivered at low doses in a continuous schedule, induces complete and partial responses in patients with refractory CLL. Dr. Ferrajoli stated, “Lenalidomide shows impressive results in helping these treatmentrefractory patients achieve complete and partial remission—and the effect looks durable.”

The investigators have enrolled 45 subjects in the ongoing study. Each patient receives lenalidomide 10mg/day for the first four weeks. The dosing is then escalated by 5 mg every 28 days to a maximum of 25 mg/day. Data on the first 35 subjects (median follow-up, 9 mo) were analyzed for the interim report. At the time of this analysis, the other 10 subjects had been on treatment for less than three months. Median subject age at enrollment was 64 years (range 49—86 yr), and the median number of prior treatments was four (range 1–15).

The investigators evaluated treatment responses according to the National Cancer Institute— Working Group criteria. They reported that 13 subjects (38%) have shown a response, with three achieving complete remission (CR, 9%), one achieving nodule response—partial remission (nPR, 3%), and nine achieving partial remission (PR, 26%). Median response duration was 11 months. Eight patients with stable disease continue to be treated. Twelve patients failed, with two dying early of complications (on days 11 and 22).

Using flow cytometry, the researchers assessed complete responders for minimal residual disease (MRD). No MRD was found in two of the three subjects. The most common toxicity was myelosuppression, with Grade >3 neutropenia and thrombocytopenia found in 17% and 14% of the subjects, respectively.

“Remarkably, our patients did not develop lymphopenia and the T-cell count remained stable or increased during treatment,” the authors noted.

The researchers reported Grade >3 fatigue, diarrhea, and tumor flare in 9%, 6%, and 6% of the patients, respectively. There were 12 serious infections, eight pneumonias, two fevers of unknown origin, one case of fatal mucormycosis, and one case of enteric cryptosporidiosis. None of the patients received routine antibiotic prophylaxis.

“The decision by the EC to designate Revlimid as an orphan medicinal product for treatment of CLL supports our efforts to move Revlimid as quickly as possible through the clinical and regulatory development process worldwide,” said Graham Burton MD, SVP, Global Regulatory Affairs and Pharmacovigilance for Celgene Corporation. “We continue to be encouraged by the growing body of published and presented data on Revlimid by key opinion leaders at major medical meetings, and based on these findings, we are committed to accelerating wherever possible our efforts to help address the unmet medical needs of patients with CLLworldwide.”

n the EU, Iceland, and Norway, Revlimid is authorized for marketing and, in combination with dexamethasone, is indicated for the treatment of multiple myeloma in patients who have received at least one prior therapy. Revlimid is also currently approved in the United States by the U.S. Food and Drug Administration and in Switzerland for multiple myeloma in patients who have received at least one prior therapy. In addition, Revlimid is approved in the United States for treatment of transfusion-dependent anemia because of low- or intermediate-1-risk myelodysplastic syndrome associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities.

Revlimid has already obtained orphan drug designation in the EU, United States, Switzerland, and Australia for the treatment of multiple myeloma and in the EU, Australia, and United States for treatment of myelodysplastic syndrome.

Treatment With Cetuximab May Enable Complete Surgical Resection of Colorectal Liver Metastases in Patients Previously Refractory to Conventional Systemic Therapy

In patients with unresectable colorectal liver metastases resistant to first-line chemotherapy, the effect of cetuximab (Erbitux) therapy on resectability is unknown.

Journal of Clinical Oncology

Dr. Rene Adam, Centre Hépato-Biliaire and the Department of Medical Oncology, Assistance Publique-Hôpitaux de Paris, France, and colleagues performed a study to determine the post-cetuximab resectability rate and to examine postoperative outcomes for these heavily pretreated patients. The results of the study were published recently in the .

Dr. Adam and colleagues evaluated 151 patients with unresectable colorectal liver metastases resistant to initial chemotherapy and subsequently treated with systemic cetuximab. Resectability rates, patient outcomes, and tumoral and nontumoral liver pathology were assessed.

A total of 27 patients underwent surgery after a median of six cycles of cetuximab plus irinotecan (N=20), oxaliplatin (N=4), or both (N=1). Eighteen patients (67%) had experienced treatment failure after at least two lines of chemotherapy before cetuximab. Twenty-five of the 27 patients who had surgery underwent hepatectomy. Postoperative mortality was 3.7% (1 of 27), with a complication rate of 50%. Histopathologic liver abnormalities were found in nine patients (36%), without specific lesions attributable to cetuximab. After a median follow-up of 16 months, 23 of 25 patients who underwent resection (92%) were alive, and 10 patients (40%) were diseasefree. Median overall survival (OS) and progression-free survival (PFS) from initiation of cetuximab therapy were 20 and 13 months, respectively.

The investigators concluded that, for colorectal liver metastases refractory to conventional chemotherapy, combination therapy with cetuximab increases resectability rates without increasing operative mortality or liver injury. They noted that the median OS and PFS of 20 and 13 months, respectively, suggest that this novel oncosurgical strategy benefits patients with previously refractory disease who respond subsequently to cetuximab.

Eric K. Rowinsky, MD, Senior Vice President and Chief Medical Officer, ImClone Systems remarked, “We are encouraged by the data from this retrospective study that demonstrate that meaningful shrinkage of metastatic disease was achieved in chemotherapy-refractory colorectal cancer patients, since complete resection of metastases offers such patients their only chance for long-term survival.”

He added, “These intriguing results in heavily pretreated patients support similar findings observed in other Phase II and III trials of Erbitux combined with irinotecan- or oxaliplatin-based chemotherapy in patients who have not received prior chemotherapy for their metastatic disease. Further prospective evaluations in both North America and Europe are ongoing or planned to evaluate the optimal means to combine Erbitux and chemotherapy to maximize the potential for complete surgical resection of colorectal liver metastases.”

Journal of Clinical Oncology

About 50% of patients with colorectal cancer will develop liver metastases during the course of their disease. Surgical resection of liver metastases is the only curative option in metastatic colorectal cancer (mCRC), and has been shown to increase five-year survival from 5% to roughly 50% in previously untreated patients. However, surgical resection is currently limited to a small proportion of patients with mCRC, predominantly because of the limited response to the best available chemotherapies. Complete surgical resection, as described in the paper, is extremely rare in patients with liver metastases from a colorectal primary tumor previously refractory to conventional systemic therapy.