Optimal Treatment Strategy with Nilotinib for Patients with Newly Diagnosed Chronic Myelogenous Leukemia in the Chronic Phase Based on Early Achievement of Deep Molecular Response (MR^4.5) : First Report from N-Road, a Phase II Study in Japan

Background: Nilotinib is a potent and selective inhibitor of BCR-ABL. In the Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients (ENESTnd) trial, frontline nilotinib therapy at 300 mg twice daily (BID) resulted in a higher rate of deep molecular response (DMR) compared to imatinib therapy in patients with chronic myelogenous leukemia in the chronic phase (CML-CP). Furthermore, in the ENESTxtend study, many patients with suboptimal response or treatment failure achieved a major molecular response (MMR) after the nilotinib dose was increased to 400 mg BID from 300 mg BID. The present study was aimed at investigating a strategy of intra-patient nilotinib dose escalation for patients with newly diagnosed CML-CP in order to achieve MR^4.5early.

Methods: N-Road is a multicenter phase II clinical study for patients with newly diagnosed CML-CP, in which nilotinib was administered at 300 mg BID for 24 months. In this study, increasing the nilotinib dose to 400 mg BID was allowed if patients satisfied the criteria for no optimal response at any time points. The criteria for no optimal response were defined as follows: BCR-ABL1 > 10% on the International Scale [IS] after 3 months, BCR-ABL1 > 1% on the IS after 6 months, BCR-ABL1 > 0.1% on the IS after 12 months, BCR-ABL1 > 0.0032% on the IS after 18 months, two consecutive losses of MMR, and two consecutive losses of MR^4.5 (BCR-ABL1 ≤ 0.0032% on the IS). The primary endpoint was the cumulative MR^4.5rate by 24 months after the initiation of nilotinib treatment.

Results:Between August 2012 and July 2015, 53 Japanese patients were enrolled, of whom 51 were evaluated in the study. The median patient age was 50 years. The ratio of men to women was 33:18. The numbers of patients with low, intermediate, high Sokal risk scores was 21 (41.2%), 21 (41.2%), and 6 (11.8%), respectively, and 3 (5.9%) had an unknown risk. The median duration of nilotinib treatment was 23.8 months (range, 4.1-26.3 months). Of the patients, 33 (64.7%) completed 24 months of treatment, 7 (13.7%) had ongoing treatment, and 11 (21.6%) discontinued treatment because of adverse events (AEs; n=4), protocol deviation (n=1), loss to follow-up (n=3), death (n=1), insufficient effect (n=1), or consent withdrawal (n=1).

The cumulative MR^4.5 rate (95% confidence interval [CI]) in the 46 evaluable patients was 52.0% (36.9-69.0%) by 24 months (Figure). The cumulative MR^4.0 and MMR rates were 60.9% (46.1-76.0%) and 83.5% (69.6-93.5%) by 24 months, respectively. Among the 46 evaluable patients, 26 satisfied the criteria for no optimal response. The dose was increased in 6 of the 26 patients but not in the remaining 20 patients for the following reasons,: hematological AEs (n=3), non-hematological AEs (n=9), achievement of MR⁴ at 18 months (n=2), patient refusal (n=4), and unknown (n=2). Although 4 patients with no optimal response achieved MR^4.5, all of them did not receive an increased treatment dose. The actual mean dose intensities in the patients with or without optimal response were 570 and 560 mg/day, respectively.

None of the patients had disease progression, and 1 patient died of an unknown cause during the study. The estimated rates (95% CI) of progression free survival and overall survival at 24 months were 98% (84-100%) and 98% (84-100%), respectively.

The most common (≥20%) non-hematological AEs of any grade were rashes (47%), headache (34.2%), fatigue (21.6%) and nausea (23.5%). The most common (≥5%) grade 3/4 laboratory abnormalities were increased lipase (10.6%), decreased phosphate (12.2%) and increased alanine aminotransferase (7.8%). Cardiovascular events were observed to be ischemic heart disease in 2 patients (3.9%).

Conclusion: In this study, it was difficult to evaluate the efficacy of nilotinib dose escalation to achieve MR^4.5 early because the dose could not be increased to 400 mg BID in many patients who did not show optimal response. However, as we were unable to increase the dose to 400 mg BID in many patients because of AEs and as nilotinib therapy demonstrated superior MR^4.5, these results might support continuous nilotinib therapy using a dosage of at least 300 mg BID for newly diagnosed CML.