Dovitinib TKI258 re disappointing, recapitulating the imatinib experience

re disappointing, recapitulating the imatinib experience.56 An administration of 400 mg twice daily emerged as the phase II dose. Subsequent phase II studies in CP and AP reported MCyR of 48% and 29% respectively.57,58 Nilotinib was approved in 2007 for CP and AP-CML. Recent followup of these patients indicate nilotinib provides a rapid Dovitinib TKI258 and durable response in these disease phases, especially in patients with prior sub-optimal response to imatinib.27,59 Resistance to Currently Approved TKIs Despite the promise of TKIs in treating CML, drug resistance does occur. Resistance can be primary or secondary/acquired. TKI failure has been linked to mutations in the ABL kinase domain that impair drug binding, increased BCR-ABL expression, and changes in drug efflux transporters that Woessner et al.
Page 4 Cancer J. Author manuscript, available in PMC 2012 May 1. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript result in low intracellular drug concentrations, particularly with imatinib.60,61 These changes can occur during progression to advanced EPO906 152044-54-7 disease phases, but they do not in and of themselves cause progression.1 In vitro mutagenesis screens have been used to profile TKIs. These studies revealed the broadest activity for dasatinib, followed by nitlotinib, while imatinib has extensive gaps in coverage, consistent with clinical data.62,63 Based on in vitro profiles, we and others have developed heatmaps of predicted in vivo activity.64 However, it is important to note that the in vivo response is more complex, involving additional parameters such as plasma protein binding and plasma peak and trough drug concentrations.
65 As a result, the correlation between in vitro predictions and clinical responses is relatively weak,66,67 with the notable exception of the T315I mutant, which is resistant to all currently approved TKIs. This poses a significant challenge to therapy because the T315I mutation is reported to represent 15-20% of all mutations.68 TKIs have transformed a previously fatal disease into a manageable chronic condition, but drug discontinuation usually results in disease recurrence, even in patients with profound responses such as MMR or PCR undetectable CML, although rare exceptions may exist.69,70 Thus, drug treatment must continue indefinitely, a significant drawback to current TKI therapy.
Consistent with these clinical observations, there is evidence that all three agents fail to eliminate primitive CML cells, and that the bone marrow environment is a potential safe-haven for these cells.71 Taken together, this suggests that minimal residual disease may be beyond the reach of our current TKI-based therapeutic arsenal. This is often referred to as disease persistence. Second-Generation TKIs in First-Line Therapy Treatment advantages of second-generation TKIs over imatinib were suggested during phase II studies, additional trials comparing these inhibitors were quickly planned and executed. The phase III trial Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients compared nilotinib 300 or 400 mg twice daily and imatinib.
After one year, MMR for either nilotinib dose was nearly double that of imatinib and CCyR was significantly higher in the nilotinib cohorts.28 Additionally, nilotinib was superior in terms of progression-free survival. As a result, the FDA granted accelerated approval of nilotinib in June 2010 for newly diagnosed CML patients.72 The Dasatinib versus Imatinib Study in Treatment-Naïve CP-CML Patients trial tested dasatinib at 100 mg daily versus imatinib 400 mg daily in newly diagnosed chronic phase patients. This report indicated a comparable advantage as seen in the ENESTnd trial regarding MMR for dasatinib over imatinib , and CCyR of 77% v. 66%.