June 20, 2011 (London, United Kingdom) — With 24 months of follow-up, nilotinib continues to show superiority over imatinib for the treatment of newly diagnosed patients with chronic myeloid leukemia (CML) in chronic phase, Andreas Hochhaus, MD, told delegates here at the 16th Congress of the European Hematology Association.
These results come from the Evaluating Nilotinib Efficacy and Safety in Clinical Trials — Newly Diagnosed Patients (ENESTnd) trial, which has already resulted in the approval of nilotinib for the first-line treatment of CML.
"Longer follow-up confirms the superiority of nilotinib over imatinib for the treatment of newly diagnosed CML in chronic phase, and nilotinib 300 mg twice daily is now the recommended treatment for newly diagnosed patients with chronic CML," Dr. Hochhaus explained.
Dr. Hochhaus, who is head of the Department of Hematology/Oncology at the University of Jena, in Germany, reported data demonstrating better major molecular responses (MMR) and complete molecular responses (CMR) with nilotinib, and limiting the development of newly detectable mutations in the target tyrosine kinase.
Previous results at 12 and 18 months of follow-up showed that nilotinib therapy was associated with better cytogenetic and molecular response rates and significant improvement in advanced disease, compared with imatinib. These new data, with a minimum of 24 months of follow-up, confirm and extend those findings, he said.
Both drugs are inhibitors of the pathogenic BCR-ABL protein, which is a constitutively active tyrosine kinase.
Trial Design
This study was a 3-group randomized trial (n = 846), in which participants were assigned to nilotinib 300 mg twice daily (n = 282), nilotinib 400 mg twice daily (n = 281), or imatinib 400 mg daily (n = 283). Planned follow-up was 5 years. The primary end point was MMR at 12 months. Secondary end points included MMR and complete cytogenetic responses (CCyR) beyond 12 months, and time to accelerated phase or blast crisis.
The trial met its primary end point of MMR at 12 months for both doses of nilotinib, compared with imatinib (P < .001), as reported in a late-breaking abstract at the 2009 meeting of the American Society of Hematology, subsequently at the 2010 annual meeting of the American Society of Clinical Oncology, and in the New England Journal of Medicine (2010;362:2251-2259).
Now, at a median of 24 months of follow-up, 92% to 95% of the patients in the 3 groups remain in the study, with 75% to 79% still on core treatment or on extension treatment for suboptimal responses or treatment failures. "That means all these patients will be followed for advanced disease and for survival," Dr. Hochhaus said.
"Less than 1% in the nilotinib 300 mg, 1% in the nilotinib 400 mg, and 4% of the patients [in the imatinib group] discontinued due to disease progression," he said. Adverse events or laboratory test abnormalities led 9% to 13% of patients to withdraw from the study.
Nilotinib Superior to Imatinib at 12 and 24 Months
Nilotinib treatment at both doses was associated with significantly superior MMR at 12 months and 24 months, compared with imatinib. This superiority in MMR was true for low, intermediate, and high Sokal risk scores at 24 months (P ≤ .003 for either nilotinib dose vs imatinib for all Sokal risk groups). "It became very clear in the development of nilotinib that the response is deeper than with imatinib," Dr. Hochhaus said. Furthermore, the CCyRs seen at 12 months were durable, and persisted through 24 months of follow-up, with an advantage for nilotinib.
Responses to Nilotinib and Imatinib at 12 and 24 Months
CMR4.0, 4.0-log reduction in BCR-ABL transcript levels, equivalent to levels ≤0.01% (International Scale)
CMR4.5, 4.5-log reduction in BCR-ABL transcript levels, equivalent to levels ≤0.0032% (International Scale)
*P = .0018 for nilotinib 300 mg vs imatinib
†P = .016 for nilotinib 400 mg vs imatinib
"A very interesting observation, which was actually not expected, was a major improvement of the evolution of the disease to accelerated phase and blast crisis very early in the course of the treatment," Dr. Hochhaus noted. "Now we have the 2-year data available, and we see 12 patients in the imatinib group [in blast crisis] vs 3 and 2 in the nilotinib groups."
He said that all patients with a lack or loss of MMR (more than 100 patients in each treatment group) were analyzed for mutations in the BCR-ABL protein. Mutations were detected in 10 patients in the nilotinib 300 mg group, 8 patients in the nilotinib 400 mg group, and 20 patients in the imatinib group. "The majority of mutations emerged in patients with high or intermediate Sokal risk scores," Dr. Hochhaus told meeting attendees.
In terms of adverse events, he said, "nilotinib was able to improve the long-lasting, low-level side effects that are a problem for most of our imatinib-treated patients. This is fluid retention, it's diarrhea, it's muscle cramps . . . [it's] nausea and vomiting. For the hematological parameters, neutropenia was improved with nilotinib." He made the "important point" that "in the second year of the treatment, only a few new myelosuppression events were observed." Adverse events that were more common with nilotinib than with imatinib were headache, pruritus, and rash.
Dr. Hochhaus summarized the results at 24 months, explaining that, compared with imatinib, nilotinib continued to demonstrate superior MMR and CMR at the 4.0-log and 4.5-log levels, and significantly fewer progressions to accelerated phase or blast crisis with treatment. MMR rates were significantly higher with nilotinib in all Sokal risk groups. Twice as many newly detectable mutations were found in the imatinib group than in either of the nilotinib groups. Patients tolerated either dose of nilotinib fairly well.
Hitting Target Harder
Approached for comment, Ross Levine, MD, from the Memorial Sloan-Kettering Cancer Center in New York City, told Medscape Medical News that "you want to make sure that the major molecular responses seen with the more aggressive tyrosine kinase inhibitors like nilotinib or dasatinib — what we saw from the first glimpse of the data a year or 6 months ago — holds up, and I think it does. There's no doubt that hitting this target harder with a newer drug will result in faster and deeper molecular responses."
Dr. Levine said that if all costs were equal, he would choose to put a patient on nilotinib for a lifetime over imatinib, but he makes 2 salient points that need to be considered. "One is that even on imatinib, the majority of patients do very well, so we have to always keep in perspective that the improvement, although real and holding up — and now extended for a long period of time — is not like it's a difference of patients doing badly and patients doing well. It's the difference between 85% to 90% of patients doing well and 90% to 95% of patients [doing well]. They each improve outcomes, but you're already starting with the standard of care being quite excellent."
Costs will probably not be equal soon, because imatinib will lose patent protection in 2015. He said a big issue in his mind, which no trial has addressed, is whether one can start with nilotinib to achieve an excellent response and then switch drugs, "especially as imatinib goes off patent" and becomes less expensive. He said people might start to ask: "Are there alternate dosing strategies that might allow me to use this better tool a little bit more specifically?"
Another strategy, he said, is to find ways to identify patients who will do better on nilotinib and reserve it for them. However, there are no molecular or clinical data to support alternative strategies at this point.
To Dr. Levine, the best argument for the use of nilotinib is the lower rate of progression of the disease to accelerated phase and blast crisis. "To me, that's the most important finding that we saw — that that's holding up at the longer follow-up," he said, and he looks forward to seeing data going out to 3 and 4 years.
He commended the study investigators for doing the mutational analyses. "The reality is that now drugs have been developed that inhibit [the appearance of] the gatekeeper mutation. That was really the final piece of the pie for us," he said. That mutation — a substitution of isoleucine for threonine at position 315 in the BCR-ABL protein — is "the one mutation that none of these drugs really inhibit well," he said, so inhibiting its development is a big step forward in staving off drug resistance.
The study was supported by Novartis. Dr. Hochhaus reports receiving research support from and being on advisory boards for Novartis, Bristol-Myers Squibb, Ariad, Pfizer, and Merck. Dr. Levine has disclosed no relevant financial relationships.
16th Congress of the European Hematology Association (EHA). PresentedJune 11, 2011
These results come from the Evaluating Nilotinib Efficacy and Safety in Clinical Trials — Newly Diagnosed Patients (ENESTnd) trial, which has already resulted in the approval of nilotinib for the first-line treatment of CML.
"Longer follow-up confirms the superiority of nilotinib over imatinib for the treatment of newly diagnosed CML in chronic phase, and nilotinib 300 mg twice daily is now the recommended treatment for newly diagnosed patients with chronic CML," Dr. Hochhaus explained.
Previous results at 12 and 18 months of follow-up showed that nilotinib therapy was associated with better cytogenetic and molecular response rates and significant improvement in advanced disease, compared with imatinib. These new data, with a minimum of 24 months of follow-up, confirm and extend those findings, he said.
Both drugs are inhibitors of the pathogenic BCR-ABL protein, which is a constitutively active tyrosine kinase.
Trial Design
This study was a 3-group randomized trial (n = 846), in which participants were assigned to nilotinib 300 mg twice daily (n = 282), nilotinib 400 mg twice daily (n = 281), or imatinib 400 mg daily (n = 283). Planned follow-up was 5 years. The primary end point was MMR at 12 months. Secondary end points included MMR and complete cytogenetic responses (CCyR) beyond 12 months, and time to accelerated phase or blast crisis.
The trial met its primary end point of MMR at 12 months for both doses of nilotinib, compared with imatinib (P < .001), as reported in a late-breaking abstract at the 2009 meeting of the American Society of Hematology, subsequently at the 2010 annual meeting of the American Society of Clinical Oncology, and in the New England Journal of Medicine (2010;362:2251-2259).
Now, at a median of 24 months of follow-up, 92% to 95% of the patients in the 3 groups remain in the study, with 75% to 79% still on core treatment or on extension treatment for suboptimal responses or treatment failures. "That means all these patients will be followed for advanced disease and for survival," Dr. Hochhaus said.
"Less than 1% in the nilotinib 300 mg, 1% in the nilotinib 400 mg, and 4% of the patients [in the imatinib group] discontinued due to disease progression," he said. Adverse events or laboratory test abnormalities led 9% to 13% of patients to withdraw from the study.
Nilotinib Superior to Imatinib at 12 and 24 Months
Nilotinib treatment at both doses was associated with significantly superior MMR at 12 months and 24 months, compared with imatinib. This superiority in MMR was true for low, intermediate, and high Sokal risk scores at 24 months (P ≤ .003 for either nilotinib dose vs imatinib for all Sokal risk groups). "It became very clear in the development of nilotinib that the response is deeper than with imatinib," Dr. Hochhaus said. Furthermore, the CCyRs seen at 12 months were durable, and persisted through 24 months of follow-up, with an advantage for nilotinib.
Responses to Nilotinib and Imatinib at 12 and 24 Months
| Cumulative incidence | Nilotinib 300 mg (% of patients) | Nilotinib 400 mg (% of patients) | Imatinib (% of patients) | P (nilotinib vs imatinib) |
| 12 months | ||||
| MMR | 55 | 51 | 27 | <.001 |
| CMR4.0 | 20 | 15 | 6 | <.001 |
| CMR4.5 | 11 | 7 | 1 | <.001 |
| CCyR | 80 | 78 | 65 | <.001 |
| 24 months | ||||
| MMR | 71 | 67 | 44 | <.001 |
| CMR4.0 | 39 | 33 | 18 | <.001 |
| CMR4.5 | 25 | 19 | 9 | <.001 |
| CCyR | 87* | 85† | 77 |
CMR4.5, 4.5-log reduction in BCR-ABL transcript levels, equivalent to levels ≤0.0032% (International Scale)
*P = .0018 for nilotinib 300 mg vs imatinib
†P = .016 for nilotinib 400 mg vs imatinib
"A very interesting observation, which was actually not expected, was a major improvement of the evolution of the disease to accelerated phase and blast crisis very early in the course of the treatment," Dr. Hochhaus noted. "Now we have the 2-year data available, and we see 12 patients in the imatinib group [in blast crisis] vs 3 and 2 in the nilotinib groups."
He said that all patients with a lack or loss of MMR (more than 100 patients in each treatment group) were analyzed for mutations in the BCR-ABL protein. Mutations were detected in 10 patients in the nilotinib 300 mg group, 8 patients in the nilotinib 400 mg group, and 20 patients in the imatinib group. "The majority of mutations emerged in patients with high or intermediate Sokal risk scores," Dr. Hochhaus told meeting attendees.
In terms of adverse events, he said, "nilotinib was able to improve the long-lasting, low-level side effects that are a problem for most of our imatinib-treated patients. This is fluid retention, it's diarrhea, it's muscle cramps . . . [it's] nausea and vomiting. For the hematological parameters, neutropenia was improved with nilotinib." He made the "important point" that "in the second year of the treatment, only a few new myelosuppression events were observed." Adverse events that were more common with nilotinib than with imatinib were headache, pruritus, and rash.
Dr. Hochhaus summarized the results at 24 months, explaining that, compared with imatinib, nilotinib continued to demonstrate superior MMR and CMR at the 4.0-log and 4.5-log levels, and significantly fewer progressions to accelerated phase or blast crisis with treatment. MMR rates were significantly higher with nilotinib in all Sokal risk groups. Twice as many newly detectable mutations were found in the imatinib group than in either of the nilotinib groups. Patients tolerated either dose of nilotinib fairly well.
Hitting Target Harder
Approached for comment, Ross Levine, MD, from the Memorial Sloan-Kettering Cancer Center in New York City, told Medscape Medical News that "you want to make sure that the major molecular responses seen with the more aggressive tyrosine kinase inhibitors like nilotinib or dasatinib — what we saw from the first glimpse of the data a year or 6 months ago — holds up, and I think it does. There's no doubt that hitting this target harder with a newer drug will result in faster and deeper molecular responses."
Dr. Levine said that if all costs were equal, he would choose to put a patient on nilotinib for a lifetime over imatinib, but he makes 2 salient points that need to be considered. "One is that even on imatinib, the majority of patients do very well, so we have to always keep in perspective that the improvement, although real and holding up — and now extended for a long period of time — is not like it's a difference of patients doing badly and patients doing well. It's the difference between 85% to 90% of patients doing well and 90% to 95% of patients [doing well]. They each improve outcomes, but you're already starting with the standard of care being quite excellent."
Costs will probably not be equal soon, because imatinib will lose patent protection in 2015. He said a big issue in his mind, which no trial has addressed, is whether one can start with nilotinib to achieve an excellent response and then switch drugs, "especially as imatinib goes off patent" and becomes less expensive. He said people might start to ask: "Are there alternate dosing strategies that might allow me to use this better tool a little bit more specifically?"
Another strategy, he said, is to find ways to identify patients who will do better on nilotinib and reserve it for them. However, there are no molecular or clinical data to support alternative strategies at this point.
To Dr. Levine, the best argument for the use of nilotinib is the lower rate of progression of the disease to accelerated phase and blast crisis. "To me, that's the most important finding that we saw — that that's holding up at the longer follow-up," he said, and he looks forward to seeing data going out to 3 and 4 years.
He commended the study investigators for doing the mutational analyses. "The reality is that now drugs have been developed that inhibit [the appearance of] the gatekeeper mutation. That was really the final piece of the pie for us," he said. That mutation — a substitution of isoleucine for threonine at position 315 in the BCR-ABL protein — is "the one mutation that none of these drugs really inhibit well," he said, so inhibiting its development is a big step forward in staving off drug resistance.
The study was supported by Novartis. Dr. Hochhaus reports receiving research support from and being on advisory boards for Novartis, Bristol-Myers Squibb, Ariad, Pfizer, and Merck. Dr. Levine has disclosed no relevant financial relationships.
16th Congress of the European Hematology Association (EHA). PresentedJune 11, 2011
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