In another reflection over the past year, OncoLink news flash would like to highlight the major pharmaceutical advancements in Oncology during the calendar year 2003. There were numerous new and important advancements in drug research and development. Some of these pharmaceutical developments that have lead the Food and Drug Administration (FDA) to either give definitive approval for or a promise of special consideration for the expedient approval of certain drugs once more data are available. Most of these new drugs have already helped thousands of patients whose options were otherwise limited. What follows is an explanation of each of these new agents and how they may help patients and physicians.
Bortezomib received FDA approval for the treatment of refractory Multiple Myeloma, a bone marrow cancer responsible for more than 14,000 cases each year. Bortezomib, a proteasome inhibitor, has a novel and unique mechanism of action making it different from all traditional chemotherapies currently available. The proteasome is actually a complex of many different enzymes that exist in all living cells. This complex functions to degrade other proteins that control cell cycle. By inhibiting the proteasome complex, multiple cellular processes, including those related to growth and survival of cancer cells, are disrupted.
Bortezomib was approved based primarily on the results of a large phase II trial that showed a response rate of 35%. Moreover, almost one in five patients experienced a clinical remission. The side effect profile was noted to be predictable and well tolerated. N Engl J Med 348:2609-2617, Jun 26, 2003, Of note, bortezomib is the first new treatment in over ten years to be approved for patients with Multiple Myeloma.
Gefitinib won FDA approval for the treatment for advanced non-small cell lung cancer (NSCLC). This approval is based on the data from the IDEAL I and IDEAL II trials. These trials, while demonstrating a significant objective response rate, failed to show a survival benefit or an improvement in disease related symptoms. Currently, gefitinib is indicated as monotherapy for the treatment of patients with advanced NSCLC after failure with both platinum based and docetaxel chemotherapies. This drug will likely create a significant impact on our society at large, as lung cancer is such a prevalent disease. It is, in fact, the leading cause of cancer deaths in the United States (an estimated 157,000 in 2003).
The Gliadel wafer received approval from the FDA for use in newly diagnosed patients with high-grade malignant gliomas (brain cancers) as an adjunct to surgery and radiation. Despite the multimodality therapeutic approach available today, the prognosis for patients with malignant glioma remains very poor. This is largely due to the high rate of recurrence at the tumor site. This newly approved therapy is a dime size biodegradable polymer (polifeprosan 20) saturated with 7.7mg of Carmustine (BCNU), a chemotherapeutic agent usually given intravenously to treat malignant gliomas. Once the brain tumor is removed, the neurosurgeon can implant up to eight wafers into the remaining tumor bed. Once implanted in the brain, they slowly dissolve and release the chemotherapy locally.
A phase III, placebo controlled, multi-center trial of newly diagnosed malignant glioma patients won this approval. Patients in this trial were randomized into two groups - wafer and placebo. All patients received standard radiation treatment. The primary end point was survival. There was a 56% increase in median survival favoring the wafer arm. Neurosurgery 41:44-49, 1997
Patients with Non-Hodgkin's Lymphoma (NHL), whose cells express the antigen CD20 now have another FDA approved therapeutic option. Bexxar is a monoclonal antibody (tositumomab) linked to a radioactive molecule (Iodine I-131). Tositumomab is able to target and bind the CD 20 antigen on NHL cells. Once bound, the antibody delivers a dose of I-131 radiation directly to the cancerous cells. Bexxar is currently approved for follicular NHL with or without transformation, refractory to rituximab.
Approval was gained based on a single arm study in patients with low grade or transformed low grade NHL where the overall response rate was 63% with a median duration of response of 25 months. J Clin Oncol. 2000 Mar;18(6):1316-23.
Two important drugs in the management of patients with cancer gained approval during the year 2003. Aloxi (palonosetrom, MGI Pharma), a 5-HT3-receptor antagonist that is effective in preventing chemotherapy induced nausea and vomiting and Emend (aprepitant, Merck), that treats and prevents delayed onset of nausea and vomiting after chemotherapy.
Orphan drug status is given to drugs that have the potential to treat life-threatening diseases that affect fewer than 200,000 patients in the United States. It gives the designated chemotherapeutic seven years of market monopoly in the US and provides access to potential grant funds for clinical research. Receiving this designation indicates that the FDA is committed to the advancement of the product and is trying to facilitate further research and development. In addition, orphan drugs often receive expedited reviews by the FDA in comparison to other drugs.
A Canadian biotech firm received FDA orphan drug designation for their product Theralux to treat patients with Chronic Myeloid Leukemia (CML). It is a photodynamic therapy technology being developed to destroy cancer ells in bone marrow or blood outside the body (ex-vivo). This drug selectively kills cancer cells when exposed to light. In addition to CML, this technology is also being evaluated for other malignancies including Non-Hodgkin's Lymphoma.
At a time when gene therapy is a dirty phrase, FDA designated Rexin-G, the first tumor targeted injectable gene therapy vector, as an orphan drug for pancreatic cancer. This decision was based on a demonstration of medical plausibility of this product for all types of pancreatic cancer. The product is currently in phase I/II trials.
Orphan drug status was given to this anti-cancer agent used for advanced kidney cancer. GTI-2040 is currently in phase II clinical trials. This drug a small oligonucleotide that acts as an antisense strand and stops tumor RNA from making proteins. When cells are unable to make certain proteins, they die. In early preclinical trials, GTI-2040 has shown a high safety profile.
This designation is a promise from the FDA that it will take all appropriate actions to expedite the development and review of the application for approval of each of these products. Often, drugs that obtained a fast track approval were once designated as orphan drugs.
Advexin selectively kills cancer cells by supplying the p53 protein in very high concentrations to the cancer tissue. P53 is a normal tumor suppressor that senses when a cell has been damaged or mutated and signals the cell to stop dividing and initiate repair mechanisms. If the cell is damaged beyond repair, p53 begins the cell death pathway to prevent this cell from dividing out of control. Two, phase II studies were done in patients with recurrent and unresectable cancer of the head and neck where Advexin has shown some efficacy in prolonging survival and time to local disease progression. There are currently ongoing phase III trials in head and neck cancer comparing this agent alone and in combination with conventional chemotherapy.
Revimid is a Thalidomide analog that appears to be more active than Thalidomide but less toxic. It has been used in early clinical trials for patients with myelodysplastic syndromes (MDS) and relapsed or refractory Multiple Myeloma. MDS are five types of malignant disorders of blood cell production that eventually lead to acute leukemia. There are an estimated 300,000 people affected with MDS worldwide.
Revimid seems to target MDS and Myeloma through a number of different mechanisms including inhibition of growth factors that may feed the cancer and suppressing growth of new blood vessels into the bone marrow. Encouraging Data with Revimid in refractory Multiple Myeloma was presented at the 45th annual American Society of Hematology meeting in December 2003 in a number of phase I and II trials. Early data supporting Revimid's efficacy in MDS was presented at the annual Chemotherapy Foundation Symposium XXI in New York November 2003. These data are preliminary and should be interpreted with caution.
Xyotax is a polyaglutamated paclitaxel that is supposed to have fewer side effects without compromise in efficacy and is targeted for NSCLC patients with poor performance status, who could not otherwise tolerate chemotherapy. Xyotax has unique polymer technology that allows it to be selectively delivered directly to the tumor in much higher concentrations. In preclinical data, higher dose of chemotherapy was noted to be delivered directly to the tumor bed as the polyaglutamated drug is trapped in the blood vessel feeding the tumor. As more chemotherapy is being delivered precisely to the cancer, the concentration of drug sensed by healthy surrounding tissues is reduced and the side effects are therefore fewer. This drug is currently in phase III clinical trials.
FDA grated the fast track status for Satraplatin for second line chemotherapy for patients with hormone-refractory prostate cancer (HRPC). Satraplatin is a member of the platinum family of chemotherapeutics, but unlike other currently available platinums, Satraplatin is an oral, not an intravenous, compound. One positive result from a 50 patient trial was already reported at ASCO 2003. These data seem to indicate a significant improvement in time to disease progression. Satraplatin is currently being investigated in other cancers such as ovarian and lung cancer.