Frontline Treatment Questions Abound as Generic Imatinib Approaches

Silas Inman @silasinman
Published: Tuesday, Jun 10, 2014
Dr. Harry P. Erba

Harry P. Erba, MD, PhD

The frontline treatment of patients with Philadelphia chromosome–positive (Ph+) chronic myelogenous leukemia (CML) continues to be debated as imatinib (Gleevec) rapidly approaches the end of its patent protection and next-generation agents continue to show efficacy in clinical trials.

Enhancing this debate is the fact that there are currently three highly effective tyrosine kinase inhibitors (TKIs) approved for the frontline treatment of patients with Ph+ chronic CML, including imatinib, and three unique therapies approved in secondary settings. Due to the depth of this armamentarium, several factors go into the decision of which therapy to utilize, including efficacy, costs, and toxicities.

In an OncLive Peer Exchange roundtable entitled “Recent Advances in MDS and CML,” moderator Harry P. Erba, MD, PhD, led a discussion on the optimal use of approved therapies across the treatment paradigm for patients with CML. The patent for the active ingredient in Gleevec expires in the United States in 2015, although other patents on certain features and processes remain in effect from 2018 to 2023, according to documents that Novartis, the drug’s manufacturer, posted on its website. Generic versions already have been launched in at least six other countries, including Canada, said Novartis.

The second-generation BCR-ABL inhibitors dasatinib (Sprycel) and nilotinib (Tasigna) demonstrated better efficacy than imatinib in the ENESTnd (Table 1) and DASISION trials (Table 2) for the first-line treatment of patients with Ph+ CML. At 24 months, the complete cytogenetic response (CCyR) rate for patients receiving dasatinib in the DASISION trial was 86%, compared with 82% with imatinib.1 Similarly, in the ENESTnd study, the 24-month CCyR rate with nilotinib was 87% at 300 mg twice daily dosing versus 77% with imatinib at 400 mg daily.2

Table 1. Four-Year Efficacy Findings From ENESTnd

  Nilotinib 300 mg BID
(n = 282)
Nilotinib 400 mg BID
(n = 281)
Imatinib 400 mg QD
(n = 283)
MMR 76% (P <.0001) 73% (P <.0001) 56%
MR4.5 40% (P <.0001) 37% (P = .0002) 23%
PFS 96.7% (P = .0497) 97.8% (P = .0074) 93.10%
OS 94.3% (P = .4636) 96.7% (P = .0498) 93.30%

BID indicates twice daily; MMR, major molecular response; MR4.5, molecular response grade 4.5; OS, overall survival; PFS, progression-free survival; QD, daily. Saglio et al. Blood. 2013;122(21; abstr 92).

Given the similar efficacy at a lower cost, imatinib remains an attractive option in the frontline setting. However, the second-generation agents are usually recommended across all settings, as a result of their increased efficacy and lesser toxicity. “I’d say that the main drivers of not using a secondgeneration TKI upfront are really economic, and I think it’s a fair discussion that’s based on limitations and things of that nature,” suggests Ruben A. Mesa, MD. “For the individual patient in the room with me, I typically advise a second-gen TKI as frontline [therapy].”

Newer Agents Prove Effective

Although there is an economic advantage with imatinib, treatment with the drug is not as well tolerated as therapy with the newer agents. Moreover, as the toxicity profile becomes more severe, patients are less likely to be compliant.


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