NEW ORLEANS—Nilotinib proved superior to imatinib in patients with newly diagnosed chronic myeloid leukemia (CML) in chronic phase, according to the results of the first head-to-head comparison of the two agents as initial treatment.
Nilotinib surpassed imatinib in every measure of treatment efficacy designated in a large, Phase III clinical trial of CML patients, including prevention of disease progression at 12 months. At the 12-month milestone, the study presented as Late-Breaking Abstract #1 at the ASH Annual Meeting by Giuseppe Saglio, MD, of the University of Turin and San Luigi Gonzaga Hospital in Italy, showed that significantly fewer patients progressed to accelerated phase or blast crisis on nilotinib than on imatinib.
Both drugs were well tolerated, and few patients on the lower dose of nilotinib discontinued because of adverse events.
Nilotinib, Dr. Saglio explained, is a highly potent and the most selective inhibitor of BCR-ABL, the only proven molecular target for CML therapy. The drug was developed as a second-generation tyrosine kinase inhibitor to follow in the footsteps of imatinib, the current standard of care in CML. For patients who stop responding to imatinib, disease progression mainly occurs in the first three years afterward and the overall survival rate is poor in these patients.
Molecular monitoring is the most sensitive measure of CML disease burden, and major molecular response (MMR) is associated with an extremely low rate of disease progression, he noted.
The Phase III, randomized, open-label, international multicenter “ENESTnd” study compared the efficacy and safety of nilotinib at either 300 mg twice daily (in 282 patients) or 400 mg twice daily (281 patients) with imatinib at 400 mg daily (in 283 patients) in newly diagnosed Philadelphia chromosome-positive (Ph+) CML in chronic phase. The 846 patients from 217 centers and 35 countries had been diagnosed with CML within six months of study entry.
Baseline demographics, disease characteristics, and Sokal scores were well balanced among the three arms, and 234 patients had a high Sokal risk score.
All the patients had at least 12 months of treatment or discontinued early. In the imatinib arm, 16% of patients were dose escalated to 400 mg twice daily, as per the protocol. The median follow-up was 14 months, and about 80% of patients in each treatment arm remained on the study.
The rate of major molecular response at 12 months in both nilotinib arms (44% at the 300 mg twice daily dose and 43% at the 400 mg twice daily dose) was twice that in the imatinib arm (22%). The nilotinib patients also achieved MMR faster (just under six months) compared with the imatinib patients (just over eight months).
The rates of complete cytogenetic response (CCyR) at 12 months were also significantly higher for both nilotinib arms (80% at 300 mg twice daily, 78% at 400 mg twice daily) compared with the imatinib arm (65%).
MMR was defined in the study as a reduction in the level of the abnormal BCR-ABL protein to 0.1% or less of the pretreatment level based on the internationally agreed standard. This can be interpreted to mean, Dr. Saglio said, that for every 1,000 cells containing BCR-ABL that were present in the blood at the start of therapy, only one cell was present at the 12-month follow-up.
A complete cytogenetic response indicates that no CML cells containing the diagnostic Ph+ chromosome can be seen in a sample of bone marrow taken from the patient. Samples for molecular response were evaluated by a single reference laboratory. Molecular response was assessed by polymerase chain reaction at baseline, monthly for three months, and every three months thereafter.
Most importantly, he said, fewer patients in either of the nilotinib groups—three patients overall—progressed to have advanced disease compared with the patients receiving imatinib (11 patients). “No patients who achieved MMR progressed to accelerated phase or blast crisis,” Dr. Saglio reported, adding that three patients who achieved CCyR on imatinib progressed to these advanced stages.
Both Drugs Well Tolerated but There Were Differences
Both drugs were well tolerated overall. Grade 3/4 neutropenia was less of a problem with nilotinib (occurring in 12% and 10% of those on low- and high-dose nilotinib, respectively) than with imatinib (occurring with 20% of that group).
Gastrointestinal effects were about half again as common with imatinib (about 30% of patients) compared with nilotinib (about 10% to 20%). Fluid retention was also substantially less common with nilotinib, with peripheral edema found in 5% of the two nilotinib groups compared with 14% in the imatinib group.
On the other hand, more than 30% of nilotinib patients at both doses developed skin rashes compared with 11% of the imatinib group.
Very Low Discontinuation Rates
Discontinuation rates were very low with both treatments: 16% for nilotinib 300 mg twice daily, 18% for nilotinib 400 twice daily, and 21% for imatinib, and were mainly due to disease progression, treatment failure, or suboptimal response. Rates of discontinuation due to adverse events or laboratory abnormalities were 5% for nilotinib 300 mg twice daily, 9% for nilotinib 400 twice daily, and 7% for imatinib.
There was no cardiac toxicity. No patients in the study showed prolongation of QT interval more than 500 milliseconds or a decrease from baseline in mean left ventricular ejection fraction. No sudden deaths occurred with either treatment.
In conclusion, Dr. Saglio said, “Nilotinib is superior to imatinib with significantly higher rates of MMR and CCyR at both 300 mg twice daily and 400 mg twice daily doses. Significantly fewer patients on nilotinib progressed compared with imatinib.” The incidence of adverse events leading to discontinuation was lowest in the nilotinib 300 mg twice daily arm. Based on these results, “nilotinib may become the new standard of care in newly diagnosed CML,” he said.
Interviewed for an OT Broadcast News “Live from ASH” podcast, Dr. Saglio said that although resistance is always a big concern, the results showed that the number of resistant cases was lower with nilotinib than with imatinib.
Asked further about what it means now for imatinib if he was saying so boldly that nilotinib should be the new standard-of-care in newly diagnosed CML patients—i.e., should all patients receiving imatinib switch to nilotinib?, Dr. Saglio said, “No. imatinib is a beautiful drug. Imatinib has changed the history of CML. This was a deadly disease….So certainly the patients who are on imatinib and responding well in terms of having reached a major molecular response should indeed continue imatinib without any problem of tolerability.
The ‘B’ Word
Speaking at an ASH news conference, one of Dr. Saglio's coauthors, Hagop Kantarjian, MD, Chair of the Leukemia Department at the University of Texas M. D. Anderson Medical Center, called the results of the nilotinib study “another new breakthrough for patients with CML.”
“The study met its endpoints, which is important for long-term prognosis of patients. CCyR at 12 months used to be standard for long-term prognosis. Most important is that the transformation rate was reduced by 40% in the first year to less than 1%. If nilotinib can reduce the risk of transformation, we will have improvement in outcome in the 15 to 20 percent of patients who would have not done as well on imatinib.”
Nilotinib appears to be the safer drug, he said, with no QT prolongation and it appears to be equally or better tolerated.
Also speaking at the news conference, another coauthor, Timothy Hughes, MD, Associate Professor of Hematology at the University of Adelaide in Australia, said that the results from the IRIS (International Randomized Study of Interferon and STI571 [imatinib] trial show that major molecular response has prognostic importance.
“Event-free survival at 18 months in the landmark analysis showed that molecular response corresponds with treatment outcome. MMR is a safe haven. Patients have a good chance of remaining stable in the long-term if they achieve MMR,” Dr. Hughes said.
Dr. Kantarjian added, “If I start with imatinib, I may lose the opportunity to control the disease better. Patients are at risk for progression in the first three years. They would benefit from nilotinib treatment.”
Should Community Oncologists Change Practice?
Whether community oncologists should change their practice immediately is a matter of debate. “We now have an additional front-line treatment of CML patients,” Dr. Kantarjian said, stating unambiguously that “in the community, doctors could change their practice to start with nilotinib.
“For practicing oncologists, nilotinib is as safe [as imatinib] and more effective for newly diagnosed cases of CML.” He said that compliance is an issue in a disease like CML that has become a chronic disease. “Physicians have to emphasize that if patients are not compliant, their outcome will be much worse than what has been published in clinical trials.”
Dr. Hughes said, “I still have enthusiasm to start patients on imatinib and then switch to nilotinib if necessary. In the next 12 months, we will have more data to see whether nilotinib will have superiority. We want to use the best treatment first to prevent [adverse] events from happening.”
Asked for his opinion, Jorge Cortes, MD, Deputy Chair of the Leukemia Department at M. D. Anderson, said, “I have been using nilotinib for five years with high response rates. It leads to fast responses and a low toxicity profile. I would not use nilotinib yet as front-line therapy until it is approved. Would I use it for myself if I needed it? Yes.”
And Francis J. Giles, MB, MD, Professor and Chief of the Division of Hematology and Medical Oncology at the University of Texas Health Science Center at San Antonio and Deputy Director of the Cancer Therapy and Research Center and Director of the Institute for Drug Development there, said that as a clinician, he considers the most important finding of the study to be the reduction of accelerated and blast phases. “If nilotinib were approved, I'd provide it to everybody. Nilotinib will become the new front-line therapy for CML. Also, anyone who does not show excellent tolerance or on-time responses to imatinib should be switched to nilotinib.”
Dr. Saglio's “very meticulously designed study” probably underestimated the possible dose intensity, Dr. Giles said.
Dr. Saglio said that patients who respond to imatinib do not need to be moved to nilotinib. “There is no benefit to moving to nilotinib. I would not give imatinib to patients who fail nilotinib since they are susceptible to similar mutations for resistance,” he said.
Dr. Kantarjian said that if a patient is resistant to nilotinib, he would prefer to go to another tyrosine kinase inhibitor, such as dasatinib or bosutinib.
Phase III Trial of Dasatinib Under Way
Other competitors to nilotinib as first-line CML treatment include dasatinib, for which a Phase III trial is now underway, with results expected this spring (perhaps at the ASCO Annual Meeting?). “It will be a happy day when we have four drugs approved for front-line therapy of CML,” said Dr. Kantarjian. Future data on dasatinib and bosutinib will show whether this is a class effect.
Dr. Saglio said, “I personally am in favor of starting patients on nilotinib. Progression of disease is what we fear the most. Fewer patients [in the study] progressed on nilotinib. This is an important achievement. Nilotinib is able to prevent progression of disease, and that is why it is my preferred choice. Now we have proof that translates into an important clinical benefit.”
He said that anecdotally he has found that patients rotated to nilotinib from imatinib ask to remain on nilotinib because of better tolerability. “As physicians, we have been too optimistic to think that all CML problems can be solved by imatinib,” he said, adding that the clinical trial continues with a planned follow-up for five years, and future studies will establish the exact best dosage of nilotinib.
The manufacturer of both drugs, Novartis, said the plan is to file worldwide applications for the approval of nilotinib as a treatment for adult patients with newly diagnosed Philadelphia-positive CML. The current approval, in approximately 80 countries, is for the treatment of adults with Ph+ CML in chronic or accelerated phase who are resistant or intolerant to prior treatment with imatinib.
“Imatinib is undoubtedly one of the best discoveries in cancer care,” Dr. Giles said. “Nilotinib has optimal binding, was one of the fastest agents to receive FDA approval, and will displace the parent drug. It's all about targeting and deliberately hitting the target. This is science, not just a paradigm shift, and will be a big step toward a cure.”
He noted that in other cancers, such as acute myeloid leukemia and non-Hodgkin's lymphoma, cures have followed a particular path. “First, therapies were developed for some complete response, and then for deeper responses,” he said. “For CML, MMR is a surrogate for cure. Once we have reproducible tumor load reductions, a cure for CML will emerge.”
Hear more about this study in the “Live from ASH” OT Broadcast News podcast (Program #4) available at oncology-times.com and on iTunes.
Nancy Berliner: ‘Watch the Data’
Also asked for her opinion about whether she thought nilotinib was likely to immediately replace imatinib as front-line therapy for patients newly diagnosed with CML, ASH 2009 President Nancy Berliner, MD, said in an OT Broadcast News podcast interview at the meeting, “I can't say that it won't become a frontline therapy. I think it will take time, because the follow-up is a year. All of the long-term data that we have is with imatinib, rather than nilotinib. And the results with imatinib are extremely good. There's not a whole lot of [comparable] data with nilotinib, and so until there's been longer follow-up and longer toxicity data, I don't think that nilotinib will immediately become the standard of care…. I think a large percentage of doctors will continue to use imatinib, both because they're more familiar with it, and because the data are more mature. I suspect that patients will have an opinion on that, and I suspect there will be lively discussions between patients and doctors about which drug to choose. But I don't think that we will see nilotinib replace imatinib immediately.”
As for the message to practicing clinicians, she said, “Watch the data.”