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New treatment approved for advanced kidney cancer
Drug doubles progression-free survival
The first treatment for advanced renal cell carcinoma has been approved by the FDA in more than a decade.
Sorafenib tosylate (Nexavar) is the first oral multikinase inhibitor that targets serine/threonine and receptor tyrosine kinases in both the tumor cell and tumor vasculature. Bayer Pharmaceuticals Corp. and Onyx Pharmaceuticals announced that the drug would be available shortly after the approval announcement on Dec. 20.
The approval was based on two studies in patients with advanced kidney cancer, which showed that patients treated with sorafenib had more time before tumor progression or death. In the larger Phase III study, most patients had previously received treatment with interleukin-2 or interferon. The median time to tumor progression or death in the sorafenib-treated arm was 167 days compared to 84 days in people not treated with the drug.
At the time of a planned interim survival analysis, based on 220 deaths, overall survival was longer for sorafenib than placebo, but the analysis did not meet the prespecified criteria for statistical significance, the companies say. They plan additional analyses at the time survival data mature.
"One of the issues here is not just the endpoint. It’s the impact on the endpoint," says Richard Pazdur, MD, FACP, director of the FDA’s Office of Oncology Drug Products, in a media teleconference. "The p-value is quite impressive. You have 100% improvement. Rarely do we see that in oncology where we have the magnitude of change on an endpoint."
FDA advisers and many other leading disease experts, in other diseases as well as in cancer alone, have emphasized that "delaying tumor growth and delaying potential symptoms is of clinical benefit and that one should not just be fixated on survival, albeit that being obviously the most important endpoint," Pazdur says.
Some common temporary side effects reported with sorafenib are rash, diarrhea, increases in blood pressure, and redness, pain, swelling, or blisters on the palms of the hands or soles of the feet.
Bayer and Onyx also have announced that a new program — the Resources for Expert Assistance and Care Helpline (REACH) — is available to answer questions about sorafenib treatment, reimbursement, and patient support. For more information, health care providers and patients may contact the REACH program at (866) NEX-AVAR [(866) 639-2827].
These other drugs were recently approved by the FDA:
• Lenalidomide (Revlimid) by Celgene Corp. The FDA has approved lenalidomide (Revlimid) for the treatment of patients with a subtype of Myelodysplastic Syndrome (MDS). The subtype is MDS patients with deletion 5q cytogenetic abnormality.
Patients with MDS may need blood and platelet transfusions and antibiotic therapy for infections. In clinical trials, patients treated with lenalidomide no longer needed transfusions, with most patients becoming independent of transfusion by three months. The transfusion-free period lasted for an average of 44 weeks.
Lenalidomide is structurally similar to thalidomide, a drug known to cause severe birth defects. Additional studies are ongoing in animals to address whether there is a risk that lenalidomide also will cause birth defects when taken during pregnancy. While these studies are under way, Celgene is marketing Revlimid under a risk management plan called RevAssist, designed to prevent fetal exposure.
Under RevAssist, only pharmacists and prescribers registered with the program will prescribe and dispense lenalidomide. The program requires patients, including female patients undergoing mandatory pregnancy testing, to give informed consent before starting lenalidomide. Physicians are to check pregnancy tests, limit prescriptions to a one-month mail supply, and report any pregnancies to the FDA. The FDA and the manufacturer will reevaluate the risk management plan when results of further animal testing for birth defects are completed.
The labeling for lenalidomide will include a Black Box Warning and a Medication Guide regarding the prevention of fetal exposure. Additional Black Box Warnings include the potential need to lower the dose due to suppressed blood counts and increased risk of blood clots. Common side effects reported with lenalidomide include thrombocytopenia, neutropenia, diarrhea, pruritis, rash, and fatigue.
• Abatacept (Orencia) by Bristol-Myers Squibb Co. The FDA has approved abatacept (Orencia), the first selective modulator of a co-stimulatory signal required for full T-cell activation, for the treatment of rheumatoid arthritis (RA).
Abatacept is indicated for reducing the signs and symptoms of RA, inducing major clinical response, slowing the progression of structural damage, and improving physical function in adult patients with moderately to severely active RA who have had an inadequate response to one or more disease-modifying anti-rheumatic drugs (DMARDs), such as methotrexate (MTX) or tumor necrosis factor (TNF) antagonists. Abatacept may be used as monotherapy or concomitantly with DMARDs other than TNF antagonists. Abatacept should not be administered concomitantly with TNF antagonists and is not recommended for use concomitantly with anakinra.
Bristol-Myers Squibb says abatacept is the first approved agent to demonstrate efficacy and safety in patients with an inadequate response to TNF antagonists, as well as those with an inadequate response to MTX.
The company does not recommend concurrent therapy with abatacept and a biologic DMARD. In controlled clinical trials, patients receiving concomitant abatacept and TNF antagonist therapy experienced more infections (63%) and serious infections (4.4%) compared to patients treated with only TNF antagonists (43% and 0.8%, respectively), without an important enhancement of efficacy.
Abatacept is administered as a 30-minute intravenous infusion at a fixed dose based on weight range approximating 10 mg/kg at day 0, week 2, week 4, and every four weeks thereafter. Infusion reactions were experienced in 9% of patients treated with abatacept and in 6% of patients treated with placebo. The most frequently reported events were dizziness, headache, and hypertension.
Abatacept is expected to be available for initial commercial use early this year.
• Conivaptan hydrochloride injection (Vaprisol) by Astellas Pharma. The FDA has approved conivaptan hydrochloride injection (Vaprisol), an arginine vasopressin (AVP) antagonist, for the intravenous (IV) treatment of euvolemic hyponatremia in hospitalized patients. Conivaptan is the first drug specifically indicated for the treatment of euvolemic hyponatremia.
Conivaptan therapy will begin with a loading dose of 20 mg IV administration followed by 20 mg administered as a continuous infusion over 24 hours. Following the initial day of treatment, conivaptan is to be administered for an additional one to three days as a continuous infusion of 20 mg/day. If serum sodium does not rise at the desired rate, conivaptan may be titrated upward to a daily dose of 40 mg, again administered in a continuous infusion.
Conivaptan is contraindicated in patients who have hypovolemic hyponatremia and in those who have hypersensitivity to any of its components. The co-administration of conivaptan with potent CYP3A4 inhibitors also is contraindicated. The most common adverse reactions reported with conivaptan administration include infusion site reactions, hypokalemia, headache, thirst, and vomiting.
• New indication for letrozole (Femara) by Novartis. The FDA has approved letrozole (Femara) in a new indication as a treatment for use after surgery in postmenopausal women with hormone-sensitive early breast cancer.
The U.S. approval was based on results of the Breast International Group (BIG 1-98) study, which were published for the first time in the Dec. 29 issue of the New England Journal of Medicine. BIG 1-98 compared the effectiveness and tolerability of letrozole vs. tamoxifen when used as initial therapy after surgery in postmenopausal women with hormone-sensitive early breast cancer.
Letrozole now is the only medicine in its class approved for use as an initial treatment immediately after surgery in postmenopausal patients with hormone-sensitive early breast cancer, and following completion of five years of tamoxifen therapy, Novartis says.