Results From the ENESTnd Extension Study: Efficacy and Safety of Patients (pts) with Chronic Myeloid Leukemia in Chronic Phase (CML-CP), Treated with Nilotinib 400 Mg Twice Daily (BID) After Suboptimal Response (SoR) or Treatment Failure (TF) to Imatinib 400 Mg Once Daily (QD) or Nilotinib 300 Mg BID

In ENESTnd, nilotinib demonstrated superior efficacy vs imatinib in pts with newly diagnosed CML-CP, including a significantly reduced rate of progression to AP/BC on treatment and a lower rate of SoR/TF. Pts in ENESTnd with SoR/TF on nilotinib 300 mg BID or imatinib could discontinue core study and enter an extension study; entrance was not allowed for intolerance. Here, we report the efficacy and safety of 49 such pts. Methods: 31 pts initially randomized to imatinib 400 mg QD (IM group) and 18 pts to nilotinib 300 mg BID (NIL group) in ENESTnd discontinued due to SoR/TF and received nilotinib 400 mg BID in this study. Progression and deaths in the extension study and after discontinuation of extension treatment have been previously reported as progression events after discontinuation of core ENESTnd treatment and in the OS analysis of ENESTnd. Results: Median time on extension treatment was 6 months (mo) for both groups (range, IM 0.2–24; NIL 1–14); 35/49 pts (71%) remain on study. Median nilotinib dose during extension treatment was equal to planned dose (800 mg/day). In the IM group, 65% of pts escalated imatinib to 400 mg BID prior to extension; 12 pts (46%) not in CCyR at extension entry and 7 pts (23%) not in MMR achieved these responses on extension treatment (table). Of these responders, 7/12 pts (58%) who achieved CCyR and 4/7 pts (57%) who achieved MMR had escalated imatinib to 400 mg BID on core study. In the NIL group, 1 pt (17%) not in CCyR at extension entry and 5 pts (29%) not in MMR, achieved this response on extension treatment. Overall, 4 pts in the IM group progressed to AP/BC (2 on extension treatment, 1 within 1 mo and the other > 12 mo after discontinuation). All 4 pts discontinued core study for TF. Overall, 1 pt in the NIL group progressed to AP/BC (< 1 mo after discontinuation of extension treatment); pt discontinued core study for SoR. The safety of nilotinib 400 mg BID was similar to that in the core study. Grade 3/4 AEs and drug-related AEs leading to discontinuation were reported in 52% and 10% of pts in the IM group. Higher rates of AEs in the first few mo of starting nilotinib in pts previously treated with imatinib were not unexpected as common AEs occur early following initial exposure. In the NIL group, grade 3/4 AEs were reported in 28% of pts and no pt discontinued due to drug-related AEs. No deaths were reported on extension treatment or ≤ 28 days of discontinuation; 4 deaths occurred > 28 days after discontinuation of treatment: 3 were CML-related (2 and 1 deaths in the IM and NIL groups, respectively) and occurred 8–10 mo after discontinuation. Conclusions: Results confirm the efficacy of nilotinib 400 mg BID for pts with CML-CP who had SoR/TF on imatinib, even after imatinib dose escalation. These results suggest that nilotinib 400 mg BID may be efficacious in pts with CML-CP with SoR/TF on nilotinib 300 mg BID, although longer follow-up is required. Whereas dose escalation of imatinib may overcome OCT-1 transporter activity in pts with correspondingly low imatinib plasma levels, nilotinib is not a substrate for OCT-1. The modest (∼16%) increase in nilotinib systemic exposure by dose escalation from 300 to 400 mg BID may benefit some patients with SoR/TF, but requires further evaluation. Currently, dose escalation of nilotinib from 300 to 400 mg BID appears safe with no additional safety signals. The extension study is ongoing and additional follow-up will provide more information moving forward.

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Hochhaus:Ariad: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Novartis Pharmaceutical: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding. Ossenkoppele:Bristol Myers Squibb: Consultancy, Honoraria; Novartis Pharmaceutical: Consultancy, Honoraria, Research Funding. Gattermann:Novartis: Honoraria, Research Funding. Hughes:Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Saglio:Bristol-Myers Squibb: Consultancy, Speakers Bureau; Novartis Pharmaceutical: Consultancy, Speakers Bureau; Pfizer: Consultancy. Larson:Novartis Pharmaceuticals: Consultancy, Honoraria, Research Funding. Hoenekopp:Novartis Pharmaceutical: Employment, Equity Ownership. Gallagher:Novartis: Employment, Equity Ownership. Yu:Novartis: Employment, Equity Ownership. Blakesley:Novartis Pharmaceutical: Employment. Kantarjian:Pfizer: Research Funding; Novartis: Research Funding; Novartis: Consultancy; BMS: Research Funding.