Hem/Onc Pharmacy 31
Pharmacy Practice News • January 2010
In Focus Imatinib
Nilotinib 300 mg bid
Nilotinib 400 mg bid
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either nilotinib arm relative to imatinib.) The CCyR rates at 12 months were 80% for 300 mg bid nilotinib (P<0.0001 vs. imatinib), 78% for 400 mg bid nilotinib (P=0.0005 vs. imatinib) and 65% for imatinib. Only two patients (0.7%) in the 300-mg nilotinib arm (P<0.001 vs. imatinib) and only one patient (0.4%) in the 400-mg nilotinib arm (P<0.004 vs. imatinib) entered AP or BC within 12 months compared with 11 patients (3.9%) in the imatinib arm. Both nilotinib and imatinib were relatively well tolerated, but there were differences in the types of side effects. Whereas grade 3 or 4 myelosuppression was generally low overall, imatinib was associated with higher rates of grade 3/4 neutropenia (20% vs. 12% and 10% for the 300- and 400-mg bid doses of nilotinib, respectively). Grade 3 or 4 nonhematologic side effects were uncommon in all groups, but when imatinib was compared with 300- or 400-mg bid nilotinib for specific side effects of any grade, rates were higher for imatinib for nausea (31% vs. 12% and 20%), muscle spasm (24% vs. 7% and 6%), diarrhea (21% vs. 8% and 7%) and vomiting (14% vs. 5% and 9%). In contrast, rash (11% vs. 31% and 26%) and headache (8% vs. 14% and 21%) were more frequently reported in the two nilotinib arms (Figure). Edema and weight gain were also more common in the imatinib arm, although overall rates were low. The most common type of edema was peripheral (any grade), reported in 14% of patients taking imatinib and 5% taking either dose of nilotinib. Grade 3 and 4 laboratory abnormalities were also observed at a low frequency overall. Although grade 3 or 4 total bilirubin elevations were more common with nilotinib than imatinib (4%
BEVACIZUMAB continued from page 22
physician in the Breast Cancer Medicine Service at Memorial Sloan-Kettering Cancer Center, New York City, pointed out that the updated AVADO study also presented at SABCS showed that the addition of bevacizumab to docetaxel as second-line therapy in patients with MBC improved PFS and overall response rate, but at 25 months, no difference in overall survival was seen. She agreed with Dr. Perez’s conclusion. “Based on results from two studies, clinicians may consider bevacizumab in combination with their choice of second-line chemotherapy for patients with metastatic breast cancer who have not received bevacizumab in the firstline setting,” Dr. Dickler said.
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31
% of Patients
NILOTINIB
30 26
24
25
21
20
21
20 14
14
15
12
11 7
10
8 6
9
8
7 5
0 Nausea
Muscle spasm
Diarrhea
Vomiting
Rash
Headache
Figure. Comparison rates of nonhematologic side effects.
‘Based on these results, we strongly believe that nilotinib may become the new standard of care in newly diagnosed CML.’ —Giuseppe Saglio, MD and 8% vs. <1%) and lipase abnormalities were more common with nilotinib (6% in either arm vs. 3% with imatinib), there was one discontinuation for nilotinib and one for imatinib due to pancreatitis. No clinically significant QTc abnormalities were observed in any group. Nearly 30% of the patients enrolled in this study were in a high Sokal risk classification, with the remaining patients relatively evenly divided between low and intermediate risk. When rates of MMR were stratified by Sokal risk, nilotinib was consistently more effective in all risk groups. Regardless of therapy, the study supported other evidence that patients with a better response, characterized by CCyR, are less likely to progress in CML. The researchers said the greater efficacy of nilotinib can be attributed to a greater specificity for the molecular target, producing a greater likelihood of an MMR. This response predicts protection from progression, which was more common for imatinib by the end of the study (4% vs. <1% for either nilotinib dose).
Confusing Picture Laura Boehnke Michaud, PharmD, BCOP, FASHP, manager of clinical pharmacy services at M.D. Anderson Cancer Center in Houston, said the results of RIBBON-2 “confuse the picture” of how to manage patients with advanced and metastatic breast cancer. A previous large randomized Phase 3 trial found no advantage in PFS for the addition of bevacizumab to capecitabine in women with advanced breast cancer who had progressed on an anthracycline and a taxane (J Clin Oncol 2005;23:792-799). Secondly, none of the trials to date with bevacizumab plus chemotherapy in breast cancer has demonstrated significant improvements in overall survival. These issues, coupled with the difficult-to-manage side effects of hypertension and blood
“We know that despite excellent results we can achieve with imatinib, progression can still occur in a small proportion of patients, and progression is associated with a poor outcome,” Dr. Saglio said. Based on these results, nilotinib further reduces the risk for progression relative to imatinib.
More Data Needed Asked to comment on the study, Richard M. Stone, MD, director of the Adult Leukemia Program at Dana-Farber Cancer Institute, in Boston, characterized the results as “encouraging,” but he did not agree with the conclusion that the study establishes nilotinib as the new standard of care in CML. He noted that nilotinib has only demonstrated superiority on the surrogate markers of MMR and CCyR. Although the responses of both parameters likely predict a decreased risk for disease progression, patients who take somewhat longer to attain the desired end points may still do well. According to Dr. Stone, the
clots, raise concern that the addition of bevacizumab may provide only modest, transient benefits for patients with MBC, Dr. Michaud suggested. “Further, recent preclinical data indicate that tumors relapsing while on antiangiogenic therapies appear to be more invasive, which may be one reason why the addition of bevacizumab has not had a positive effect on [overall] survival. These data, of course, need to be confirmed in clinical trials, but bring to light significant concerns with this agent,” she said. “Everyone is grappling with how to apply results of RIBBON-2 and to decide what is in the best interest of patients,” Dr. Michaud added. “I have some concerns about giving a clearly toxic drug to potentially compromised patients that does not extend survival.
decreased rate of progression to AP disease was the most compelling finding in favor of nilotinib over imatinib. “The story is complicated, and it is not clear that this study has generated the type of data that warrants an immediate change in practice. We need longer follow-up that continues to show meaningful clinical differences, such as risk for progression, beyond the surrogate end points,” Dr. Stone said. “These are strong findings that do predict nilotinib has the potential to emerge as the better firstline agent, but we are not there yet.”
Hem/Onc Pharmacist Urges Caution Asked for his comment, Casey B. Williams, PharmD, hematology/oncology clinical coordinator and residency director, Kansas University Medical Center, Kansas City, concurred with Dr. Stone. “I am also not convinced that this data warrants an immediate change in practice. We have at least eight years of followup information to go on with imatinib from the IRIS trial and the results have been quite impressive. Overall survival is approximately 85% with imatinib, and actually climbs to around 93% when only CML-related deaths and those prior to stem cell transplant are considered,” Dr. Williams reported. From the pharmacy perspective, one variable of interest is price. Dr. Williams noted that nilotinib “is a lot more expensive than imatinib,” but these results may change pricing for both imatinib and nilotinib. Pricing strategies are particularly difficult to predict because the same pharmaceutical company, Novartis, markets both drugs. In any event, Dr. Williams characterized nilotinib as “a promising alternative to imatinib as a first-line agent,” but “I am not ready to change my practice just yet.” —Ted Bosworth
The drug is going to be studied as maintenance therapy in this population, which is also of concern, but should be systematically studied.” Dr. Michaud also stated that the decision to add bevacizumab should be individualized and discussed fully with each appropriate patient, including mention of all the concerns she cited. The bottom line is that bevacizumab has difficult-to-manage toxicities, does not prolong survival, and is also expensive. Dr. Michaud is not convinced that this drug should be used second-line, as in the RIBBON-2 trial. “However, each patient should be presented with the available information and given the opportunity to decline or accept the therapy.” —Alice Goodman