In a review of new drugs to hit the market, speaker Maribel Pereiras, PharmD, BCOP, BCPS, referred to 2010 as “quite the year for prostate and breast cancer.” Pereiras, a clinical assistant professor at Ernest Mario School of Pharmacy, Rutgers University, and a clinical oncology pharmacist with Hackensack University Medical Center, New Jersey, reviewed newly approved anticancer agents sipuleucel-T (Provenge), cabazitaxel (Jevtana), eribulin (Halaven), and denosumab (Xgeva) for pharmacists attending the annual meeting of the Hematology/Oncology Pharmacy Association. She also discussed dabigatran etexilate (Pradaxa), an anticoagulant recently approved to prevent stroke and embolism in patients with atrial fibrillation, which she included because she anticipates some oncologists using it off been approved at the time of the meeting and was included in a discussion of investigational drugs, which we will present in an upcoming issue.
Sipuleucel-T is the first approved therapeutic vaccine in oncology and is indicated for men with asymptomatic or minimally symptomatic castration-resistant prostate cancer (CRPC). The drug is an autologous cellular immune therapy, manufactured for each individual patient in a process that involves training the patient’s T cells to attack prostate cancer cells. Approval was based on data from the randomized IMPACT trial, which reported a 4.1- month improvement in overall survival (OS) for men treated with sipuleucel-T compared with those given placebo (25.8 vs 21.7 mo, respectively; P = .032).
The process for treating patients with sipuleucel-T requires coordination among multiple individuals. To assist clinicians, Dendreon announced the ON Call program. After a physician orders the drug, Dendreon returns a treatment schedule. Once the patient confirms availability for the proposed dates, Dendreon approves the order.
Sipuleucel-T is administered in three 1-hour infusions spaced 2 weeks apart. For each cycle, the patient undergoes leukapheresis to procure antigen-presenting cells (APCs) from his immune system, which are shipped to a Dendreon facility. The laboratory combines the APCs with prostatic acid phosphatase, found in 95% of prostate cancer cells, and granulocyte-macrophage colony-stimulating factor. In 2 to 3 days, the APC is considered active and shipped back to the institution for administration at the designated time.
The drug arrives at the time of the appointment in a special insulated container within a cardboard box. Upon receipt, the pharmacist can open the box and remove the container to verify product and patient information but Pereiras said not to open the inside container until Dendreon has issued a Cell Product Disposition Form and the patient has been prepped. Universal precautions should be taken when handling the drug, which normally appears slightly pink and cloudy.
Pereiras said 70% of patients have mild infusion reactions, consisting of chills, fatigue, fever, and pain. To mitigate adverse effects, she recommended giving patients acetaminophen and diphenhydramine ~30 minutes prior to infusion. Most reactions occur within 1 day of treatment and typically last no longer than 2 days. If a patient reacts during the infusion, Pereiras said the treatment can be stopped and resumed if the reaction is not serious. She said to “think twice” before using steroids. “There have been some serious events reported, including a cerebrovascular accident.”
Formal data are not available on possible drug interactions with sipuleucel- T. Because it works by boosting the immune system, Pereiras said, “Anything given to suppress the immune system could counteract that, like chemotherapy or corticosteroids.”
Due to the time-consuming and complicated manufacturing process, sipuleucel-T is currently available only at the 50 centers involved in the original clinical trials. No more than 2000 patients were expected to receive sipuleucel- T in 2010, but Pereiras said Dendreon plans to expand its manufacturing capacity soon.
In the summer of 2010, the FDA approved cabazitaxel, a microtubule inhibitor, for patients with metastatic CRPC that has progressed on or following treatment with a docetaxel-containing regimen. “Cabazitaxel works to bind free tubulin to promote their assembly into stable microtubules but then inhibits the disassembly, so [that] it ultimately freezes the cell within mitosis,” Pereiras explained. The patient receives a 25-mg/m2 injection of cabazitaxel every 3 weeks and takes 10 mg of oral prednisone daily throughout treatment.
View larger version
In the phase 3 TROPIC study, patients randomly assigned to receive cabazitaxel plus prednisone demonstrated superior median OS, progression-free survival, and response compared with patients given mitoxantrone and prednisone (Table 1). Although cabazitaxel is a taxane, Pereiras said it has low affinity for P-glycoprotein –mediated efflux pumps associated with multidrug resistance and might be a means of overcoming taxane resistance in some patients.
Cabazitaxel contains polysorbate 80 and the diluent contains ~13% ethanol. As a result, severe hypersensitivity reactions are possible, and patients should be premedicated with an antihistamine, corticosteroid, and a histamine-2 antagonist approximately half an hour before administration. The prescribing instructions also recommend antiemetic prophylaxis as needed.
“It is really nice that we have something efficacious, but from an adverse event perspective, there really are some things to be concerned about,” she warned. In TROPIC, high rates of neutropenia, myelosuppression, and anemia were observed in the cabazitaxel arm.
Gastrointestinal symptoms are common, with ~6% of patients experiencing diarrhea. Deaths have been reported from severe treatment-related diarrhea, and doses should be reduced for any patient with ≥grade 3 diarrhea. “This is an important counseling point to patients,” said Pereiras. “They need to know to stay hydrated, use antidiarrheals, and not go the whole weekend before contacting us.”
In TROPIC, nearly 30% of patients treated with cabazitaxel suffered grade 3/4 neutropenia and 7% developed neutropenic fevers, which might have been dose-related. Cabazitaxel is therefore contraindicated in patients with neutrophil counts ≤1500 cells/mm3. Pereiras said it is important for clinicians to stay on top of monitoring blood counts during therapy. Patients aged ≥65 years appear more prone to neutropenia-related fevers and deaths, and some clinicians recommend primary prophylaxis with granulocyte colony-stimulating factor for any patient with an elevated risk of febrile neutropenia.
Some patients in TROPIC’s cabazitaxel arm experienced neurotoxicities or suffered cardiac-related events. A clinical trial is under way to investigate the effect of cabazitaxel on QTc intervals.
Cabazitaxel is extensively metabolized by the liver via CYP 3A4/5 and, to a lesser extent, CYP 2C8. CYP 3A inhibitors or inducers might affect area under the curve concentrations and are to be avoided. A phase 1 trial is evaluating cabazitaxel in patients with hepatic impairment. “Some dose-adjustment may be needed in patients with hepatic dysfunction,” Pereiras cautioned. Excretion via the renal pathway is minimal, but because no data are available on patients with creatinine clearance <30 mL/min, she said patients with renal dysfunction should be monitored.
A 2-step dilution process is used for cabazitaxel. Pereiras cautioned that in preparing the drug, it is essential to use a polyvinyl chloride–free bag and an inline filter.
Eribulin Mesylate (Halaven)
Eribulin is from a novel class of agents called halichondrins. “It is approved for metastatic breast cancer, specifically in those patients that have already had at least 2 chemotherapy regimens, which should have included an anthracycline and a taxane,” said Pereiras.
Eribulin, a synthetic analogue of a sea sponge chemical, is a nontaxane, microtubule dynamics inhibitor. “But when you get down to the basics, it’s just like any other taxane—it works on the microtubules,” she said. Unlike traditional microtubule inhibitors that halt cell division by stabilizing the microtubules, eribulin achieves cell cycle arrest by preventing microtubule growth without affecting microtubule shortening.
In the EMBRACE study, a phase 3 randomized trial that compared eribulin with the physician’s choice of chemotherapy, OS was significantly improved for women who received eribulin (13.1 vs 10.6 mo, respectively; P = .041). Median PFS and the overall response rate were also better for the eribulin arm, but women taking eribulin had a shorter duration of response.
The recommended dose for eribulin is 1.4 mg/m2 administered via intravenous push over 2 to 5 minutes on days 1 and 8 of a 21-day cycle. No premedications are required. “It can be given as straight drug or can be further diluted in normal saline. It is not compatible with dextrose,” she emphasized.
Eribulin is minimally metabolized by CYP enzymes. “[There is] some inhibitor effect on CYP 3A4 and on P-glycoprotein, but this is thought to be minimal,” she said. No formal studies have evaluated eribulin in patients with renal dysfunction, but one pharmacokinetic study looked at patients with mild to moderate hepatic dysfunction. Pereiras directed clinicians to the package insert for specific recommendations on adjusting the eribulin dose for patients with hepatic or renal problems.
At least one-quarter of patients in EMBRACE experienced anemia, weakness/ tiredness, alopecia, nausea, and constitution. Most (82%) patients developed neutropenia, with 4% experiencing grade 3/4 febrile neutropenia. “Blood counts should be closely monitored and dose adjustments should be made if a patient experiences neutropenic fever or grade 4 neutropenia,” said Pereiras.
Eribulin extends the QT interval, and she recommended monitoring in patients at risk of cardiovascular events, especially patients with a wider QT interval at baseline. She also advised clinicians to check magnesium potassium levels and correct any deficiencies prior to therapy.
Grade 3/4 peripheral neuropathy, observed in several patients, was cited as the most common reason for discontinuation. For these patients, Pereiras suggested withholding eribulin and reintroducing once neuropathy falls to grade 2.
“Oncology is not just about the chemotherapy agents we work with day in and day out. It’s also about supportive care,” said Pereiras, as she moved on to denosumab, a drug recently ap proved to prevent skeletal-related events (SREs) in patients with solid tumors and bone metastases. It is marketed as Prolia to treat osteoporosis in postmenopausal women.
Denosumab is a human monoclonal antibody with affinity for the receptor activator of nuclear factor kappa-β ligand (RANKL), a protein expressed by osteoblasts that is critical to osteoclast formation. Denosumab binds to RANKL, interrupting osteoclast formation and thus preventing bone resorption.
View larger version
In 3 large, randomized trials, denosumab was compared with zoledronic acid (ZA), a bisphosphonate commonly used to prevent SREs. One trial enrolled 2046 patients with breast cancer; another, 1901 men with prostate cancer; and the third, 1776 patients with various solid tumors and multiple myeloma. In each study, a smaller percentage of patients in the denosumab arm experienced an onstudy SRE, and denosumab delayed the time to first on-site SRE (Table 2).
Xgeva is administered subcutaneously at a 120-mg dose every 4 weeks. Pereiras warned against confusing this with the dose for Prolia, which is 60 mg every 6 months. Obviously, Xgeva and Prolia should not be administered concurrently because they are the same drug. Xgeva does not need to be reconstituted, and no dose adjustment is required for patients with renal dysfunction.
“It is generally well tolerated, but there are a few things to be aware of,” said Pereiras. “It can cause more electrolyte disturbances than ZA, particularly with regard to calcium creatinine clearance <30 mL/min.” These patients and those on dialysis were more likely to develop severe hypocalcemia, and she said electrolytes should be monitored. For all patients, she recommended evaluating calcium levels and correcting, if necessary, before treatment, as well as having patients take calcium and vitamin D supplements.
Osteonecrosis of the jaw occurs in an estimated 2.2% of patients treated with denosumab. “It’s very important to counsel our patients on good oral hygiene and avoiding extensive dental procedures while on denosu mab,” Pereiras said. Other adverse events include dermatitis, eczema, rash, limb pain, cataracts, and hypercholesterolemia.
Pereiras said researchers are keen to study whether denosumab has anticancer properties. She noted that during bone resorption, growth factors believed to spur tumor growth are released, so preventing bone resorption might theoretically contribute to better outcomes. This is only a hypothesis, however, and denosumab is only approved to prevent bone loss.
Dabigatran Etexilate (Pradaxa)
Dabigatran, an oral direct thrombin inhibitor, is approved to prevent stroke and systemic embolism in pa tients with nonvascular fibrillation. Pereiras said clinicians who treat cancer are increasingly likely to en counter patients already taking it. “It may get another indication which would open it up to some of our oncology patients,” she said.
In explaining its mechanism of action, Pereiras said, “We have an intrinsic pathway and an extrinsic pathway. Thrombin is affected by both pathways and works to convert fibrinogen to fibrin, which results in and aids thrombus formation. Dabigatran inhibits thrombin and therefore thrombus formation.”
While the drug is not yet indicated to prevent deep-vein thrombosis (DVT) or pulmonary embolism (PE)—thromboembolic events common in patients with cancer—the RECOVER study concluded that dabigatran (n = 1274) was noninferior to warfarin (n = 1265) at preventing recurrent DVT/PE. RECOVER enrolled patients aged ~55 years with good renal function and found that, although dose adjustments were required for patients with renal impairment, dabigatran had a good safety profile.
Adverse effects included bleeding events and gastrointestinal effects, such as dyspepsia and gastritis-like symptoms. Nearly 17% of patients in the dabigatran arm experienced a bleeding event, and 1.5% of bleeding events were considered life-threatening. Only 5% of patients in each arm had cancer, however, and Pereiras said, “It’s going to be hard to say if right now we can carry that information over to our oncology patients.”
Dabigatran is not an inhibitor or inducer of the CYP 450 enzyme system but is a substrate of P-glycoprotein. Data suggest drug–drug interactions with rifampin, ketoconazole, verapamil, amiodarone, and clopidogrel. Pereiras noted that the package insert includes special instructions for converting patients to and from warfarin therapy and to or from parenteral anticoagulation.
“A very interesting tidbit that came out a short time ago is that once a bottle is opened, it’s only good for 30 days, so make sure you use your blister packs,” said Pereiras. She said the manufacturer has not explained what happens “between day 29 and day 30” and expressed concern as to whether the drug is slowly losing efficacy over the 30-day period.
Pereiras disclosed that she has received consulting fees from EUSA Pharma and fees for non–continuing education services from Sancusco