correspondence
Ponatinib in Philadelphia Chromosome–Positive Leukemias To the Editor: Cortes et al. (Nov. 7 issue)1 report the results of their study of ponatinib, which had been withdrawn from the market because of an excessive risk of severe vascular events, but now can be prescribed under a risk-evaluation and mitigation strategy in the United States. The initial dose of 45 mg daily in this study involving patients with Philadelphia chromosome–positive leukemias is questionable, since the maximum concentration at the 15-mg dose and the trough blood concentration at the 30-mg dose exceeded the 40-nM concentration, at which complete suppression of the emergence of BCR-ABL1 mutations is achieved.2 Furthermore, that dose was linked to a boxed warning regarding arterial thrombosis and hepatotoxicity. In phase 1 and phase 2 studies of ponatinib, toxicity rates were dose-dependent, and the pharmacokinetic and pharmacodynamic activities of the 30-mg and 45-mg doses were roughly equivalent (a half-life of 22 hours achieved at doses as low as 30 mg daily).1,2 The experience with ponatinib casts serious doubts over the continuing trend of administering targeted drugs at the maximum tolerated dose instead of at the biologically active dose. A change in methods of drug development is warranted to prevent more lifesaving drugs from becoming unavailable to patients with cancer. Alfonso Quintas-Cardama, M.D. M.D. Anderson Cancer Center Houston, TX [email protected] Dr. Quintas-Cardama reports receiving speaking fees from Ariad Pharmaceuticals, Novartis, Bristol-Myers Squibb, and Teva. No other potential conflict of interest relevant to this letter was reported. 1. Cortes JE, Kim D-W, Pinilla-Ibarz J, et al. A phase 2 trial
of ponatinib in Philadelphia chromosome–positive leukemias. N Engl J Med 2013;369:1783-96. 2. Cortes JE, Kantarjian H, Shah NP, et al. Ponatinib in refractory Philadelphia chromosome–positive leukemias. N Engl J Med 2012;367:2075-88. DOI: 10.1056/NEJMc1315234
The Authors Reply: Quintas-Cardama comments on the issue of the most appropriate dosing for a
new drug. The principle of administering drugs to a “biologically active” dose is an attractive but complex endeavor, and it is difficult to apply with existing data. With ponatinib, the 50% inhibitory concentration required to inhibit proliferation of cells transfected with BCR-ABL and various kinase domain mutations varies considerably from 0.5 nM (in unmutated BCR-ABL) to 36 nM (in BCR-ABL with the E255V mutation).1 Inhibition of the emergence of resistant clones is indeed achieved in vitro at concentrations of 40 nM of ponatinib when starting with cells transfected with native BCR-ABL, but resistant clones may be recovered at concentrations of up to 320 nM in models starting with a T315I mutation.1 For patients with other mechanisms of resistance, such as most instances of resistance without mutations, these principles offer little or no guidance, and good predictive biomarkers are lacking. In animal models1 and in the patients in our study, there is a dose–response correlation, and mutations emerge in some patients when none would be predicted to emerge on the basis of concentrations alone.2 Further research in this area is indeed warranted. Jorge E. Cortes, M.D. M.D. Anderson Cancer Center Houston, TX
Moshe Talpaz, M.D. University of Michigan Ann Arbor, MI
Hagop Kantarjian, M.D. M.D. Anderson Cancer Center Houston, TX Since publication of their article, the authors report no further potential conflict of interest. 1. O’Hare T, Shakespeare WC, Zhu X, et al. AP24534, a pan-
BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell 2009;16:401-12. 2. Deininger MW, Shah NP, Cortes JE, et al. Impact of baseline (BL) mutations, including low-level and compound mutations, on ponatinib response and end of treatment (EOT) mutation analysis in patients (Pts) with chronic phase chronic myeloid leukemia (CP-CML). Blood 2013;122:652. abstract. DOI: 10.1056/NEJMc1315234
n engl j med 370;6 nejm.org february 6, 2014
577
The New England Journal of Medicine Downloaded from nejm.org at RUTGERS UNIV ALEXANDER LIBRARY on August 11, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
Ponatinib in Philadelphia Chromosome–Positive Leukemias To the Editor: Cortes et al. (Nov. 7 issue)1 report the results of their study of ponatinib, which had been withdrawn from the market because of an excessive risk of severe vascular events, but now can be prescribed under a risk-evaluation and mitigation strategy in the United States. The initial dose of 45 mg daily in this study involving patients with Philadelphia chromosome–positive leukemias is questionable, since the maximum concentration at the 15-mg dose and the trough blood concentration at the 30-mg dose exceeded the 40-nM concentration, at which complete suppression of the emergence of BCR-ABL1 mutations is achieved.2 Furthermore, that dose was linked to a boxed warning regarding arterial thrombosis and hepatotoxicity. In phase 1 and phase 2 studies of ponatinib, toxicity rates were dose-dependent, and the pharmacokinetic and pharmacodynamic activities of the 30-mg and 45-mg doses were roughly equivalent (a half-life of 22 hours achieved at doses as low as 30 mg daily).1,2 The experience with ponatinib casts serious doubts over the continuing trend of administering targeted drugs at the maximum tolerated dose instead of at the biologically active dose. A change in methods of drug development is warranted to prevent more lifesaving drugs from becoming unavailable to patients with cancer. Alfonso Quintas-Cardama, M.D. M.D. Anderson Cancer Center Houston, TX [email protected] Dr. Quintas-Cardama reports receiving speaking fees from Ariad Pharmaceuticals, Novartis, Bristol-Myers Squibb, and Teva. No other potential conflict of interest relevant to this letter was reported. 1. Cortes JE, Kim D-W, Pinilla-Ibarz J, et al. A phase 2 trial
of ponatinib in Philadelphia chromosome–positive leukemias. N Engl J Med 2013;369:1783-96. 2. Cortes JE, Kantarjian H, Shah NP, et al. Ponatinib in refractory Philadelphia chromosome–positive leukemias. N Engl J Med 2012;367:2075-88. DOI: 10.1056/NEJMc1315234
The Authors Reply: Quintas-Cardama comments on the issue of the most appropriate dosing for a
new drug. The principle of administering drugs to a “biologically active” dose is an attractive but complex endeavor, and it is difficult to apply with existing data. With ponatinib, the 50% inhibitory concentration required to inhibit proliferation of cells transfected with BCR-ABL and various kinase domain mutations varies considerably from 0.5 nM (in unmutated BCR-ABL) to 36 nM (in BCR-ABL with the E255V mutation).1 Inhibition of the emergence of resistant clones is indeed achieved in vitro at concentrations of 40 nM of ponatinib when starting with cells transfected with native BCR-ABL, but resistant clones may be recovered at concentrations of up to 320 nM in models starting with a T315I mutation.1 For patients with other mechanisms of resistance, such as most instances of resistance without mutations, these principles offer little or no guidance, and good predictive biomarkers are lacking. In animal models1 and in the patients in our study, there is a dose–response correlation, and mutations emerge in some patients when none would be predicted to emerge on the basis of concentrations alone.2 Further research in this area is indeed warranted. Jorge E. Cortes, M.D. M.D. Anderson Cancer Center Houston, TX
Moshe Talpaz, M.D. University of Michigan Ann Arbor, MI
Hagop Kantarjian, M.D. M.D. Anderson Cancer Center Houston, TX Since publication of their article, the authors report no further potential conflict of interest. 1. O’Hare T, Shakespeare WC, Zhu X, et al. AP24534, a pan-
BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell 2009;16:401-12. 2. Deininger MW, Shah NP, Cortes JE, et al. Impact of baseline (BL) mutations, including low-level and compound mutations, on ponatinib response and end of treatment (EOT) mutation analysis in patients (Pts) with chronic phase chronic myeloid leukemia (CP-CML). Blood 2013;122:652. abstract. DOI: 10.1056/NEJMc1315234
n engl j med 370;6 nejm.org february 6, 2014
577
The New England Journal of Medicine Downloaded from nejm.org at RUTGERS UNIV ALEXANDER LIBRARY on August 11, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
