ORLANDO, FL—A question on many minds has been what will happen to imatinib when it goes off-patent. Data from trials of second-generation tyrosine kinase inhibitors (TKIs) presented here at the American Society of Hematology Annual Meeting give more evidence that dasatinib may be a candidate to take its place.
The results of Intergroup Trial S0325 of newly diagnosed patients with chronic myeloid leukemia in chronic phase (CML-cp) show that dasatinib at 100 mg induced deeper molecular responses in a head-to-head trial against the first-generation imatinib tyrosine kinase inhibitor at 400 mg, although there was no statistically significant difference between the two drugs in 12-month progression-free and overall survival.
First author Jerald P. Radich, MD, Medical Director of the Research Trials Office at Fred Hutchinson Cancer Research Center and Professor of Medicine at the University of Washington School of Medicine, who presented data from the study in a Late Breaker session, said that cost will be no small factor in the future, considering that high-cost dasatinib will be competing against a generic imatinib.
The differences in response and toxicity favoring dasatinib may be outweighed by a price tag that some estimate will be twice that of a generic imatinib.
In the study Dr. Radich reported (senior author was Brian J. Druker, MD), the comparison of imatinib and dasatinib in newly diagnosed patients with CML-cp showed dasatinib inducing deeper molecular responses at 12 months, but not significantly higher rates of greater than a 4-log or 4.5-log reduction in BCR-ABL.
“This is just more evidence that dasatinib 100 mg is more efficacious than imatinib 400 mg in newly diagnosed chronic-phase CML,” Dr. Radich said, adding that clinical follow-up is continuing to study whether the short-term deeper molecular response seen with dasatinib will translate into improved long-term outcomes.
Dasatinib is an established second-line treatment for patients with CML-CP who are resistant, intolerant to, or have a suboptimal response to imatinib. In the randomized, open-label Phase II S0325 trial, patients with newly diagnosed CML-CP were randomized to oral daily imatinib 400 mg, or oral daily dasatinib 100 mg. Four North American cooperative groups participated in S0325: SWOG, ECOG, CALGB, and NCIC-CTG.
The primary endpoint was a greater than 4-log reduction in BCR-ABL transcript at 12 months. Data here were on 246 evaluable patients, 123 in each study arm.
Hasford intermediate- and high-risk scores were 35% and 30%, respectively; 60% of the patients were male; and median age was 49. Dr. Radich noted that this is young for CML patients, but added that ages ranged from 18 to 90.
Eighteen dasatinib (15%) and 13 imatinib (11%) patients discontinued treatment because of a variety of toxicities; 11 patients (3 dasatinib and 8 imatinib) discontinued due to refusal; and 36 others (12 dasatinib and 24 imatinib) for other reasons, mainly physician or patient concerns about inadequate response, recurrence, or progression.
Dr. Radich reported 12-month complete cytogenetic remission rates of 82% for dasatinib versus 69% for imatinib, but added that cytogenetic complete response data were available for only 51% of patients.
Molecular response by peripheral blood PCR at 12 months was deeper in the dasatinib arm—a median 3.3-log reduction in BCR-ABL transcript level vs a 2.8-log reduction with imatinib. But the proportions achieving a greater than 4-log or 4.5-log reduction did not differ significantly, he said.
Overall survival and progression-free survival were similar in the two arms, with very few deaths, relapses, or progressions.
Among patients with hematologic complete response, the two-year relapse-free survival rate was 97% in the dasatinib arm and 95% in the imatinib arm.
Compared with DASISION, ENESTnd
Dr. Radich said the S0325 results were “remarkably similar” to two randomized imatinib-comparison trials in CML-cp also reported at the ASH meeting. (Dr. Radich also noted that “the DASISION trial had a much better acronym” than S0325.)
The data for the DASISION Trial (Abstract 206) with 519 patients, sponsored by Bristol-Myers Squibb (Kantarjian et al: NEJM 2010; 362:2260-2270) were reported at the meeting by Neil P. Shah, MD, PhD, of the University of California, San Francisco School of Medicine.
At 18 months, confirmed complete cytogenetic response rates in DASISION were 78% for dasatinib vs 70% for imatinib. Major molecular response rates at any time during the study were 57% for dasatinib and 41% for imatinib.
Dr. Radich also cited 18-month results for the ENESTnd trial, sponsored by Novartis Pharma AG, comparing nilotinib with imatinib in 846 patients with CML-CP, presented here (Abstract 207) by Timothy P. Hughes, MD, of Royal Adelaide Hospital in Australia. The overall best complete cytogenetic response rates were 85% for nilotinib at 300 mg bid, 82% for nilotinib at 400 mg bid, and 74% for imatinib at 400 mg. Overall best major molecular response rates were 66% for nilotinib at 300 mg bid, 63% for nilotinib at 400 bid, and 40% for imatinib at 400 mg.
“One of the things people were worried about prior to this meeting was that maybe there were long-term complications that we didn't know about in these drugs, but these papers that were presented here show no signal of increasing toxicity with a longer follow-up in these patients.,” Dr. Radich said. “So I think that now we've come to a point where we can really talk about using these as primary therapies without having reservations.”
Dasatinib, however, was associated with more Grade 3/4 toxicity, he noted. There were no fatal toxicities in the study. The more common Grade 3 and 4 toxicities were hematologic, including thrombocytopenia in 18% and 8% of dasatinib and imatinib patients, respectively. A variety of Grade 4 nonhematologic toxicities were reported for 6% of dasatinib patients, but none for imatinib.
An additional 30% and 17% of dasatinib and imatinib patients had a variety of Grade 3 nonhematologic toxicities, respectively, while another 57% and 79% had nonhematologic Grade 1-2 toxicities.
Pleural effusion of any grade was reported for 11% and 2% of patients receiving dasatinib and imatinib, respectively, and less than 2% in either arm had Grade 3 problems.
“Surprisingly, more Grade 3 and 4 diarrhea occurred in the dasatinib arm,” Dr. Radich said. Edema was more common in the imatinib arm, while pleural effusions were more common in the dasatinib arm. Nausea and muscle pain were both more common in the imatinib arm, with headache more common in the dasatinib arm.
Seven patients have died, all more than eight months after entering the study. Three dasatinib patients died: one at eight months after disease progression to blast crisis, one from lung cancer diagnosed 10 months after dasatinib started, and one in an automobile accident.
Two imatinib patients died of CML, and two others (ages 70 and 75 at treatment start) of cardiac arrest unrelated to CML or treatment.
In an interview after his presentation, Dr. Radich said a major issue will be what happens when imatinib goes off patent in 2015.
“That's going to be a game changer, because for many health systems and many countries, it's going to be so much cheaper. The real challenge will be integrating the second-generation TKIs with the cheaper imatinib.”
In the clinic, he said, this could mean starting CML patients on imatinib and switching over to the more expensive second-generation drug if they don't get good responses; or starting with the expensive second-generation drug, getting a great response and then going on maintenance with the imatinib forever.
Scientific Program Co-Chair: Practice-Changing Study
Robert A. Hromas, MD, Co-Chair of the Scientific Program and Program Committee (with David T. Scadden, MD), predicted in an interview after Dr. Radich's report that the study will be practice changing.
“It's now the second trial that shows that the newer BCR-abl kinase inhibitors—in this case dasatinib—are more effective than the first BCR-abl kinase inhibitor, imatinib, and that you get deeper and longer lasting responses with similar, or even less toxicity than imatinib,” he said. They should therefore be considered up front, as first choice, in treatment of CML.
“I think that this should be practice-changing.”
Dr. Hromas, Chief of Hematology-Oncology at the University of New Mexico, said that most patients with imatinib-resistant CML—unless they have the specific T-315I mutation—will respond to nilotinib or dasatinib.
He called Dr. Radich's trial well conducted and well powered, and noted that extensive molecular testing was done.
“The remarkable thing is [this study's] strength of the molecular responses in dasatinib over imatinib in this trial, and it's been shown a number of times that those molecular responses ultimately correlate with clinical outcome,” he said.
“As hematologists and oncologists treating chronic leukemia, we should be using the newer BCR-abl kinase inhibitors up front.”
That would include nilotinib and dasatinib, the two FDA-approved second-generation TKIs, he said.
Dr. Hromas added that the experimental agent ponatinib is generating some excitement as it inhibits BCR-abl kinases with the T315I mutation.
Anecdotally, Dr. Hromas mentioned that patients who are not compliant with imatinib treatment—because of GI upset, for example—are more likely to develop the T315I mutation.
Mikkael Sekeres: Key is Decreased Rate of Transformation
Asked for his opinion, OT Clinical Advisory Editor for Hematology/Oncology Mikkael Sekeres, MD, commented, “What has moved these second-generation tyrosine kinase inhibitors to front-line therapy for chronic-phase CML, in my mind, is the decreased rate of transformation to accelerated phase and blast crisis CML compared with imatinib—both acceptable interim markers for survival.”