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ENESTnd: Evaluating Nilotinib Efficacy and Safety in Clinical Trials–Newly Diagnosed Patients

Richard A. Larson, Philipp le Coutre, Josy Reiffers, Timothy Hughes, Giuseppe Saglio, Pascal Edrich, Albert Hoenekopp, Neil Gallagher, Hagop Kantarjian, Andreas Hochhaus on behalf of the ENESTnd Investigators.

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ENESTnd: Evaluating Nilotinib Efficacy and Safety in Clinical Trials–Newly Diagnosed Patients

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  1. Richard A. Larson, Philipp le Coutre, Josy Reiffers, Timothy Hughes, Giuseppe Saglio, Pascal Edrich, Albert Hoenekopp, Neil Gallagher, Hagop Kantarjian, Andreas Hochhaus on behalf of the ENESTnd Investigators Comparison of nilotinib and imatinib in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP): ENESTnd beyond one year ENESTnd: Evaluating Nilotinib Efficacy and Safety in Clinical Trials–Newly Diagnosed Patients

  2. Background • Nilotinib is highly potent and the most selective inhibitor of BCR-ABL1 • Imatinib is the current standard of care for CML • ENESTnd is a global, multicenter, randomized phase 3 study of nilotinib 300 mg BID and 400 mg BID vs imatinib • Results reported at ASH 2009 from the primary analysis were from a median follow-up of 13.8 months2 • Results reported here today are with a median follow-up of approximately 18.5 months • Manley P, et al. Biochim Biophys Acta. 2009. • Saglio G, et al. NEJM.E-pub ahead of print 5 June 2010.

  3. Study Design and Endpoints R A N DO M I Z ED * Nilotinib 300 mg BID (n = 282) • N = 846 • 217 centers • 35 countries Nilotinib 400 mg BID (n = 281) Imatinib 400 mg QD (n = 283) Follow-up 5 years • Primary endpoint: MMR at 12 months • Key secondary endpoint: Durable MMR at 24 months • Other endpoints: CCyR by 12 months, time to MMR and CCyR, EFS, PFS, time to AP/BC on study treatment, OS including follow-up *Stratification by Sokal risk score 3

  4. Eligibility Criteria • Ph+ CML-CP within 6 months from diagnosis • No prior therapy for CMLexcept: • HU/anagrelide • < 2 weeks of imatinib (9-13% across arms) • Age ≥ 18 years • ECOG performance 0-2 • QTcF <450 msec • Adequate organ function

  5. Definitions of Patient Populations Intention-to-treat (ITT) population (N=846) used for efficacy analyses All randomized patients are included and analyzed by assigned treatment Safety population (N=836) used for safety analyses All randomized patients who received at least one dose of study medication are included and analyzed by treatment they received 5

  6. Definition of Endpoints Response assessments are collected during study treatment MMR: BCR-ABL ≤ 0.1%IS Unavailable sample considered as lack of response Atypical transcripts at baseline considered as lack of response (8 patients) CCyR: No Ph+ metaphases out of  20 Unavailable or insufficient sample considered as lack of response FISH not used for assessment Progression to AP/BC on treatment Progression defined as per ELN 2006 criteria1 Overall survival includes data from follow-up after discontinuation of treatment 1. Baccarani M, et al. Blood. 2006;108(6):1809-20. 6

  7. Patient Disposition *Investigator assessment of criteria #Patients were required to discontinue nilotinib 300 mg BID for suboptimal response but could remain on nilotinib 400 mg BID Data cut-off: 2Jan2010

  8. Treatment Duration and Average Dose • Patients had at least 16 months of treatment or discontinued early • Dose intensity was close to planned dose across all arms • Nilotinib dose escalation was not permitted in either arm • Imatinib dose escalation to 800 mg/day permitted for suboptimal response or treatment failure (24%) Data cut-off: 2Jan2010

  9. Primary Endpoint - MMR Rate at 12 Months (ITT Population)* P < .0001 P < .0001 % MMR n = 282 n = 281 n = 283 *Saglio G, et al. NEJM. E-pub ahead of print 5 June 2010. Data cut-off: 2Sept2009

  10. Cumulative Incidence of MMR* Pts Overall best response Best response by 12 mo. 100 Nilotinib 300 mg BID Nilotinib 400 mg BID Imatinib 400 mg QD 282 281 283 90 80 66% (P < .0001) 70 55% (P < .0001) 60 62% (P < .0001) Patients with MMR (%) 50 51% (P < .0001) 40 40% 30 27% 20 10 0 24 0 3 6 9 12 15 18 21 Time Since Randomization (mo) *ITT population Data cut-off: 2Jan2010

  11. MMR Rates at 18 and 24 Months (Patients with PCR assessment) % MMR n = 178 n = 175 n = 172 n = 49 n = 48 n = 48 Data cut-off: 2Jan2010

  12. Rates of Molecular Response of  0.0032%IS* by 12 Months and Overall P < .0001 30% P < .0001 21% P < .0001 20% 17% P < .0001 % With  0.0032% IS 11% 10% 7% 6% 1% n = 282 n = 281 n = 283 n = 282 n = 281 n = 283 0% Month 12 Overall Nilotinib 300 mg BID Nilotinib 400 mg BID Imatinib 400 mg QD *ITT population 12 Data cut-off: 2Jan2010

  13. CCyR Rates* by 12 Months and Overall P < .001 P < .0001 P = .017 P < .001 % CCyR n = 282 n = 281 n = 283 n = 282 n = 281 n = 283 • Among patients who had a cytogenetic assessment at 18 months (n = 442/846), the rates of CCyR were: • 99%, 99%, and 89% for nilotinib 300 mg BID, 400 mg BID, and imatinib *ITT population 13 Data cut-off: 2Jan2010

  14. Nilotinib 300 mg BID Nilotinib 400 mg BID Imatinib 400 mg QD 20 P = .006 P = .003 15 12 Number of Patients 10 4.2% 5 2 1 0.4% 0.7% 0 Progression to AP/BC on Study Treatment* With a median follow-up of 18.5 months. P-values are based on log-rank test stratified by Sokal risk group vs imatinib for time to AP/BC. *ITT population Data cut-off: 2Jan2010

  15. Overall Grade 3/4 Myelosuppression Any Time on Study % of Patients Data cut-off: 2Jan2010

  16. Study Drug-Related Non-laboratory Adverse Events (≥ 10% in Any Group) Data cut-off: 2Jan2010

  17. Study Drug-Related Fluid Retention (All Grades) • Grade 3/4 AEs were rarely observed in any treatment arm (<1%) • There was no clinically relevant prolongation in QT interval or decrease in LVEF 17 Data cut-off: 2Jan2010

  18. Laboratory Abnormalities • One patient in the imatinib arm and one in the nilotinib 400 mg BID arm discontinued the study due to acute pancreatitis 18 Data cut-off: 2Jan2010

  19. Overall Survival* Includes Deaths After Discontinuation *ITT population 19 Data cut-off: 2Jan2010

  20. ENESTnd Beyond 1 Year • With longer follow-up, rates of MMR and CCyR remain superior for nilotinib vs imatinib • Molecular responses are continuing to deepen over time • There continues to be fewer progression events and fewer deaths with nilotinib vs imatinib • Nilotinib at both doses was generally well-tolerated • Longer follow up supports nilotinib as a new standard of care in patients with newly diagnosed CML

  21. ENESTnd Contributing Investigators Argentina: B Moiraghi, M Perez; Austria: R Greil, P Valent; Belgium: L Noens, A Bosly, G Verhoef, M André, P Martiat; Brazil: MA Zanichelli, C Souza, V Hungria, V Colturato, M Conchon, A Nonino; Canada: JH Lipton, D Forrest, M Lalancette, R Delage, M-L Savoie; Colombia: G Quintero, M Gomez; Czech Republic: H Klamova, E Faber; Denmark: H Fredriksen, H Vestergaard, O Weis Bjerrum, C Marcher; Egypt: H Kamel, H Elzawam; Finland: K Porkka, K Remes; France: J-L Harousseau, A-P Guerci-Bresler, F Rigal-Huguet,M Tulliez, D Guyotat, M Gardembas, M Escoffre, L Legros, F Guilhot, D Rea, F-E Nicolini, T Facon, J-Y Cahn, A Johnson-Ansah, A Charbonnier; J Reiffers, Germany: N Gattermann, C Scheid, D Niederwieser, OG Ottmann, K Blumenstengel, J Duyster, T Brümmendorf, M Kneba, F Stegelmann, P Schafhausen; Hong Kong: Y-L Kwong; Hungary: T Masszi; Italy: G Fioritoni, G Alimena, F Nobile, E Pungolino, G Rosti, M Gobbi, E Abruzzese, M Petrini, A Bosi, AM Carella, EM Orlandi, F Ferrara, F Lauria, S Amadori, F Di Raimondo, A Levis, M Tiribelli, P Leoni, A Rambaldi, M Martelli, B Rotoli, F Pane; Japan: M Hino, I Matsumura, M Kurokawa, Y Kanda, C Nakaseko, O Miura, I Jinnai, Y Maeda, K Ohnishi, T Nagai, S Miyawaki, K Imai, A Tomita, K Ohishi, K Usuki, M Okada, Y Miyazaki, A Kimura, K Miyamura, S Nakao, K Toba, S Okamoto, S Chiba, N Tsukamoto, N Takahashi, Y Kobayashi, K Ohyashiki, T Kawaguchi, M Imamura, A Matsuda, J Ishikawa; Malaysia: T Chuan Ong; Mexico: J Kassack, D Gómez Almaguer; Netherlands: GJ Ossenkoppele; Norway: T Gedde-Dahl, H Hjorth-Hansen; Poland: K Kuliczkowski, S Kyrcz-Krzemieñ, W Jedrzejczak, A Dmoszynska, J Starzak-Dwozdz, J Holowiecki; Russia: A Turkina,T Pospelova, A Zaritsky; Singapore: LP Koh, YT Goh; Slovakia: L Demitrovicova, M Mistrik; South Africa: G Cohen, LM Dreosti, V Louw, P Ruff, N Novitzky; South Korea: S-K Sohn, H-J Kim, C-W Jung, K-H Lee, S-Y Park; Spain: F Cervantes, F Marin, J Hernandez Boluda, C Boque, R de Paz, J Batlle, RF Rodriguez, E Conde, J Odriozola, M Perez Encinas, C Cañizo, A Julia Font, B Heredia, P Giraldo, P Lopez, JL Steegman, MA Echeveste Gutierrez, M Sanz Alonso, S del Castillo, R Pérez-López, P Herrera, MJ Rodriguez; Sweden: L Stenke, S Lehmann, B Simonsson, H Wadenvik, B Markevärn, K Myhr Eriksson, M Bjoreman, J Richter, ASjälander; Switzerland: Y Chalandon; Taiwan: M-C Wang, M Yao, L-Y Shih; Thailand: S Jootar, U Bunworasate; Turkey: B Sahin, B Ulkü, B Undar, R Haznedar; United Kingdom: D Marin, T Holyoake, J Byrne, G Smith; United States: I Flinn, S Goldberg, M Kalaycio, R Gingrich, J Burke, T Ervin, T Shea, B Powell, C Alemany, K Kolibaba, G Guzley, M Guerra, WG Harker, J Davis, W Edenfield, E Arrowsmith, H Koh, L Fehrenbacher, R Paquette, A Al-Janadi, L Akard, G Robbins, M Savin, D Schlossman, D Richards, W Berry, M Woodson, C Siegrist, J Glass, M Heaney, H Wallach; Venezuela: J Lopez

  22. Back-up

  23. Baseline Patient Characteristics Data cut-off: 2Sept2009

  24. Overall MMR Rates according to Sokal Score* % MMR *ITT population Data cut-off: 2Jan2010

  25. Confirmed* CCyR Rates by 12 Months** P < .0001 P < .0001 % CCyR **ITT population * Confirmed by subsequent bone marrow assessment Data cut-off: 2Jan2010

  26. Suboptimal Response and Treatment Failure at 12 Monthsa,b % of patients n = 282 n = 281 n=283 n = 282 n = 281 n=283 aBased on modified ELN 2009 Recommendations; Baccarani et al, JCO. 2009; bITT population Suboptimal response: PCyR at 12 months Treatment failure: < PCyR at 12 months or loss of CHR, loss of CCyR, progression to AP/BC, or clonal evolution by 12 months 26 Data cut-off: 2Sept2009

  27. Outcome After Imatinib Dose Escalation 68 patients received imatinib 400 mg BID 10 patients achieved MMR after dose escalation 13 patients achieved CCyR after dose escalation without MMR 18 patients with CCyR prior to dose escalation did not achieve MMR after dose escalation 27 patients did not achieve MMR or CCyR after dose escalation 27 Data cut-off: 2Jan2010

  28. QT Prolongation and LVEF Changes • There was no clinically relevant prolongation in QT interval or decrease in LVEF 28 Data cut-off: 2Jan2010

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