Efficacy and Safety Of Ponatinib Following Failure Of Nilotinib In Patients With Chronic Phase Chronic Myeloid Leukemia (CP-CML) In The PACE Trial

• Published in: Blood 2013-11, Vol.122 (21), p.2738-2738
• Main Authors: Kantarjian, Hagop M., Cortes, Jorge E., Kim, Dong-Wook, Pinilla-Ibarz, Javier, le Coutre, Philipp D., Paquette, Ronald, Chuah, Charles, Nicolini, Franck E., Apperley, Jane F., Khoury, H Jean, Talpaz, Moshe, DiPersio, John F., DeAngelo, Daniel J., Abruzzese, Elisabetta, Rea, Delphine, Baccarani, Michele, Müller, Martin C., Gambacorti-Passerini, Carlo, Lustgarten, Stephanie, Rivera, Victor M., Clackson, Tim, Turner, Christopher D., Haluska, Frank G., Guilhot, Francois, Deininger, Michael W., Hochhaus, Andreas, Hughes, Timothy P., Goldman, John M., Shah, Neil P.
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V122.21.2738.2738

Information is generally lacking regarding the efficacy and safety of subsequent TKIs after failure of nilotinib. This post-hoc analysis explored the efficacy and safety of ponatinib, a potent oral pan-BCR-ABL inhibitor, following failure of nilotinib in CP-CML patients in the phase 2 PACE trial. The PACE trial enrolled 449 patients, including 270 with CP-CML. Patients had to be resistant or intolerant to dasatinib or nilotinib, or have the T315I mutation at baseline. The primary end point in CP-CML was MCyR at any time within 12 months after treatment initiation. The trial is ongoing. Data as of 1 April 2013 are reported, with a minimum follow-up of 18 months for patients remaining on study. The efficacy and safety of ponatinib (45 mg QD) in 106 CP-CML patients following failure of nilotinib as the most recent prior anticancer therapy, irrespective of other TKI therapy, is presented (Group N). Eleven patients who experienced failure of nilotinib but received ≥1 anticancer therapy, other than hydroxyurea or anagrelide, prior to ponatinib treatment were excluded from the analyses. Data are also presented for 2 subsets of Group N: 33 patients whose only TKI therapy was imatinib followed by nilotinib (Group I-N), and 68 patients whose only TKI therapy was imatinib, then dasatinib, and then nilotinib (Group I-D-N). An analysis of cross-intolerance was also conducted in 43 patients with prior nilotinib treatment at any time who discontinued nilotinib due to intolerance. Baseline characteristics are shown in the table. Group I-N tended to be younger, with less time since diagnosis versus Group I-D-N. At the time of analysis, 59%, 64%, and 56% of patients in Groups N, I-N, and I-D-N remained on study. The most common reasons for discontinuation were adverse events (AEs; 12%, 12%, 13%) and progressive disease (9%, 6%, 9%) in Groups N, I-N, and I-D-N. Efficacy endpoints are shown in the table. In Group N, MCyR was observed in patients with the following nilotinib-resistant mutations at baseline: Y253H, 1/2 (50%); E255K, 5/6 (83%); T315I, 12/22 (55%); F359V, 3/7 (43%); F359C, 1/2 (50%); F359I, 2/3 (67%). The most common treatment-related AEs were thrombocytopenia (38%, 33%, 40%), rash (35%, 30%, 37%), and dry skin (35%, 42%, 31%) in Groups N, I-N, and I-D-N. Serious cardiovascular, cerebrovascular, and peripheral vascular AEs occurred in 6%, 4%, and 2% of patients in Group N (treatment-related: 3%, 1%, 2%). Forty-four of 184 patients discontinued prior nilotinib at