BETTER DRUGS FOR CML

December 14, 2009 — Nilotinib (Tasigna) demonstrated greater efficacy than imatinib (Gleevec) in adult patients with newly diagnosed Philadelphia-chromosome-positive chronic myeloid leukemia (CML) in the chronic phase, according to results of a new study.

These findings, which were presented during a late-breaking abstract session here at the American Society of Hematology 51st Annual Meeting, found that, at both the 300 and 400 mg doses, nilotinib induced significantly higher and faster rates of major molecular response and complete cytogenetic response than imatinib 400 mg, the current standard of care in patients with newly diagnosed CML.

Nilotinib is currently approved for second-line use in CML in patients who have become resistant or intolerant to imatinib. However, as previously reported by Medscape Oncology, results from a phase 2 trial presented earlier this year showed that when it was used as a first-line therapy, nilotinib produced responses that were superior and faster than those seen historically with imatinib.

The latest results come from a direct head-to-head comparison of the 2 drugs used as first-line therapy, and they show that the responses to nilotinib were significantly better than those seen with imatinib.

At 12 months, major molecular responses were observed in 44% of patients receiving nilotinib 300 mg twice daily and in 22% who received imatinib 400 mg once daily (P < .0001). Results were similar for nilotinib 400 mg twice daily dose (43% vs 22%; P < .0001).

"Nilotinib is a highly potent and the more selective inhibitor of BCR-ABL with respect to imatinib, which is the current standard of care in CML," said lead author Giuseppe Saglio, MD, from the University of Turin in Italy. "We know that despite the excellent results that can be achieved with imatinib, progression can still occur in a small proportion of patients. Disease progression is associated with a poor outcome in terms of overall survival."

The findings of this study show that nilotinib is superior to imatinib, with significantly higher rates of molecular response and complete cytogenetic response, said Dr. Saglio. "Nilotinib was superior across all Sokal risk groups. Based on these results, we believe that nilotinib will become the new standard of care in newly diagnosed patients."

Possibly Practice-Changing?

"This is an interesting study and it may alter practice," said Richard A. Van Etten, MD, PhD, director of the Cancer Center at Tufts Medical Center, in Boston, Massachusetts. "We knew a long time ago that this trial was probably going to have a superior outcome — a major molecular response and complete cytogenetic response earlier than imatinib. We've known that from many individual studies, and the same is probably true for dasatinib."

Dr. Van Etten, who was not involved in the study, noted that a key point of this study is that it defined "a vulnerable window in that first year, when an excess of patients on imatinib progress."

It is not known at this time whether nilotinib will receive approval as a first-line therapy, but for the practitioner treating patients with CML, "one would have to say that this is pretty persuasive," he told Medscape Oncology.

However, he pointed out that the rate of progression with imatinib in this trial was unusually high. In other studies, the rate of progression on a standard dose of imatinib was much lower. "This is a randomized trial, so we have to accept the data, but this difference is possibly explained by the high Sokal risk index in this trial," he said.

Dr. Van Etten also explained that patients who are progressing can be recognized and salvaged. "One possibility is to aggressively monitor patients on imatinib and then switch them when they fail to meet molecular milestones."

Cost will become a consideration. "Imatinib will also be going off patent in 2014 or 2015, and then the cost will drop dramatically; that is a factor that has to be considered," he added.

Shorter Response Time, Lower Rate of Progression

The Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients (ENESTnd) is a phase 3 randomized, multicenter, multinational study that compared the efficacy and safety of nilotinib 300 or 400 mg twice daily with imatinib 400 mg once daily in adult patients with newly diagnosed chronic-phase Philadelphia-chromosome-positive CML.

The cohort consisted of 846 patients who received their CML diagnosis within a 6-month period and who were stratified by Sokal risk score and randomized on a 1:1:1 basis to nilotinib 300 mg twice daily (n = 282), nilotinib 400 mg twice daily (n = 281), or imatinib 400 mg once daily (n = 283). The primary end point of the study was the rate of major molecular response at 12 months, and the major secondary end point was the rate of complete cytogenetic response by 12 months, based on bone marrow cytogenetics.

The median age of the cohort was 47 years, and 28% of patients had high-risk Sokal scores, noted Dr. Saglio. The minimum treatment duration was 12 months or early discontinuation, and median follow-up was 14 months.

The median time to major molecular response was shorter for patients who received nilotinib 300 mg (5.7 months) or nilotinib 400 mg (5.8 months) than for those who received imatinib 400 mg (8.3 months). At 12 months, the rates of complete cytogenetic response were significantly higher for nilotinib at either 300 mg (80% vs 65%; P < .0001) or 400 mg (78% vs 65%; P = .0005).

Progression to advanced disease was also lower for nilotinib 300 mg (2 patients) and nilotinib 400 mg (1 patient) than it was for imatinib 400 mg (11 patients).

Molecular and Cytogenetic Response Rates Overall and by Sokal Score

Response Rates	Nilotinib, 300 mg Twice/Day, n = 282	Nilotinib, 400 mg Twice/Day, n = 281	Imatinib, 400 mg Once/Day, n = 283
Molecular response rate
6 months	93 (33%)	83 (30%)	34 (12%)
12 months	125 (44%)a	120 (43%)a	63 (22%)
High-risk Sokal molecular response rate (12 months)	32/78 (41%)	25/78 (32%)	13/78 (17%)
Complete cytogenetic response rate
6 months	188 (67%)	177 (63%)	126 (45%)
12 months	226 (80%)a	219 (78%)b	184 (65%)
Estimated rate of progression to accelerated phase/blast crisis at 12 months	<1%c	<1%d	4%

^a P < .0001
^b P = .0005
^c P = .0095
^d P = .0037

All treatments were well tolerated, and discontinuation rates because of adverse events or laboratory abnormalities were similar across the 3 study groups (7% for nilotinib 300 mg, 11% for nilotinib 400 mg, and 9% for imatinib 400 mg).

The superior efficacy and favorable tolerability profile of nilotinib, compared with imatinib, suggests that nilotinib could become the standard of care in newly diagnosed CML.

Related Studies Show Similar Results

In 2 related studies, researchers reported that nilotinib and dasatinib might be more effective than imatinib as first-line therapies for chronic-phase CML, according to preliminary findings that were presented from 2 phase 2 trials underway at the University of Texas M.D. Anderson Cancer Center in Houston.

"More patients taking nilotinib or dasatinib are achieving complete responses more quickly than they do on either of the 2 daily doses of imatinib," said Jorge Cortes, MD, professor and deputy chair of the Department of Leukemia and lead author of both studies, in a statement.

Dr. Cortes and colleagues found that 96% of patients receiving nilotinib and 94% receiving dasatinib reached a complete cytogenetic response at 6 months, compared with 54% of those receiving imatinib 400 mg a day and 85% of those receiving imatinib 800 mg.

In the dasatinib trial, a major molecular response has been reached in 35 of 62 patients (70%), with 5 (10%) achieving complete molecular response. Similarly, a major molecular response has been reached in 32 of 65 patients (63%) in the nilotinib trial, with 12 patients (24%) achieving complete molecular response.

According to Dr. Cortes, adverse events have been manageable to date and similar to those seen with imatinib.

The nilotinib study was funded by Novartis. The MD Anderson Cancer Center studies were funded by Novartis and Bristol-Myers Squibb. Dr. Saglio reports relationships with Novartis and Bristol-Myers Squibb. Several of his coauthors report relationships with Novartis, Bristol-Myers Squibb, and Wyeth.

American Society of Hematology ASH 51st Annual Meeting: Abstracts 341 and 338. Presented December 8 and December 7, 2009.