CLL Brad Kahl, MD Professor of Medicine

Transcription

1 CLL 2016 Brad Kahl, MD Professor of Medicine

2 Disclosures Advisory Committee Consulting Agreements Contracted Research Roche Laboratories Inc, Takeda Oncology Bristol-Myers Squibb Company, Celgene Corporation, Genentech BioOncology Abbott Laboratories

3 A simplistic (and outdated) approach to CLL Chlorambucil - GA101 >80 yrs <60 yrs FCR yrs 58% age 70 at diagnosis yrs Age at CLL Diagnosis Olmsted County MN, BR Shanafelt T. ASH Education Book. 2013;;2013:

4 Frontline management of CLL One must take a more sophisticated approach to CLL now Consider IgVH mutational status (particularly in younger patients) Consider cytogenetic risk profile (CLL FISH panel) 13q, trisomy 12, 11q, 17p Consider ibrutinib as a frontline option for any patient regardless of age or risk profile A complicated discussion with patient Lacking comparative data Lacking long term outcome data with ibrutinib

5 Dec 10th, 2015 NEJM

6 RESONATE-2 Previously untreated CLL or SLL Requiring therapy Age > 65 Randomized to ibrutinib or chlorambucil 420 mg/daily until PD or intolerance 0.5 mg/kg days 1 & 15 q28 days x 12 cycles Primary endpoint: PFS

7 RESONATE-2 PFS benefit seen in all subgroups ORR 86% vs. 35% CR 4% vs. 2% OS benefit for ibrutinib 98% vs. 85% at 2 yrs Toxicity c/w prior reports

8 ASH updates. Longer term follow up Resonate 2. Abstract #234 Barr et al, Sat 5:15. PCYC Abstract #233 O Brien et al, Sat 5:00 Ibrutinib efficacy unaffected by mutational status.

9 CLL frontline treatment considerations PRO: Ibrutinib efficacy excellent with longer term follow up why not simply give that to everyone as initial therapy? No need to worry about age, mutational status, 17p No new safety signals emerging CON: Ibrutinib remissions tend to be shallow Low CR rate (18% in abstract 233) Need continuous therapy Still not many patients with 5+ years experience Cost

10 Annual cost of CLL management is projected to reach $5.13 billion by % increase from 2011 For patient initiating frontline oral therapy in 2016, projected lifetime CLL cost will increase from $147,000 to $604,000 Medicare out-of-pocket costs increase from $9,200 to $57,000 J Clin Oncol, online

11 CLL patient requiring frontline therapy Young (<65) and fit Mutated IgVH (no 17p) FCR vs. ibrutinib Unmutated IgVH (no 17p) Ibrutinib vs. FCR 17p del Ibrutinib Ordinary CLL (age 65-80) Mutated IgVH (no 17p) BR vs. ibrutinib Unmutated IgVH (no 17p) Ibrutinib vs. BR 17p del Ibrutinib Elderly CLL (age >80) Ibrutinib vs. obinutuzumab-chlorambucil Ibrutinib if 17p del

12 Philip A. Thompson, Constantine S. Tam, Susan M. O Brien, William G. Wierda, Francesco Stingo, William Plunkett, Susan C. Smith, Hagop M. Kantarjian, Emil J. Freireich, and Michael J. Keating

13 Kirsten Fischer, Jasmin Bahlo, Anna Maria Fink, Valentin Goede, Carmen Diana Herling, Paula Cramer, Petra Langerbeins, Julia von Tresckow, Anja Engelke, Christian Maurer, Gabor Kovacs, Marco Herling, Eugen Tausch, Karl- Anton Kreuzer, Barbara Eichhorst, Sebastian Böttcher, John F. Seymour, Paolo Ghia, Paula Mariton, Michael Kneba, Clemens- Martin Wendtner, Hartmut Döhner, Stephan Stilgenbauer, and Michael Hallek

14 Davide Rossi, Lodovico Terzi- di- Bergamo, Lorenzo De Paoli, Michaela Cerri, Guido Ghilardi, Annalisa Chiarenza, Pietro Bulian, Carlo Visco, Francesca R. mauro, Fortunato Morabito, Agostino Cortelezzi, Francesco Zaja, Francesco Forconi, Luca Laurenti, Ilaria Del Giudice, Massimo Gentile, Iolanda Vincelli, Marina Motta, Marta Coscia, Gian Matteo Rigolin, Alessandra Tedeschi, Antonio Neri, Roberto Marasca, Omar Perbellini, Carol Moreno, Giovanni Del Poeta, Massimo Massaia, Pier Luigi Zinzani, Marco Montillo, Antonio Cuneo, Valter Gattei, Robin Foà, and Gianluca Gaidano

15 What should you quote a younger, mutated IgVH patient considering FCR? Based upon the 3 data sets 75% likelihood of sustained remission at 5 years 60% likelihood of sustained remission at 8 years Based upon other data sets ~5-8% risk of tmds/aml Pros: therapy done in 6 months Cons: risk for OI and 2 nd cancers

16 Basis for frontline strategy in 2016 FCR better than BR in CLL 10 Better for mpfs (54 vs. 43 months) More toxic BR just as efficacious in patients >65 or with comorbidities Note impact of mutational status Chlorambucil-obinutuzumab better than Chl-R or Chl alone in CLL 11 OS advantage vs. Chl alone

17 Basis for frontline strategy CLL 10 (Eichhorst et al, Lancet Oncol) CLL 11 (Goede et al, NEJM)

18 E1912: FCR vs. Ibrutinib-R Frontline Therapy Age 18-70

19 Alliance Study: A Frontline study patients 65

20 R/R CLL In 2016 most R/R patients have had prior FCR, BR, chlorambucil, etc. Ibrutinib FDA approved for R/R CLL in 2/14 ORR 90%, 3-yr PFS ~60% (Byrd et al, Blood 2015) Idelalisib-Rituximab approved for R/R CLL in 7/14 ORR 81%, 1-yr PFS ~ 60% (Furman et al, NEJM 2014) Venetoclax approved for R/R CLL with 17p- in 5/16 ORR 79%, 1-yr PFS 72% (Stilgenbauer et al, Lancet Oncol 2016)

21 N = 107 Venetoclax 400 mg po QD ( ) No TLS ORR 79%, CR 8% No unexpected toxicity

22 Venetoclax ASH Update Abstract #637. Jones et al. Venetoclax for ibrutinib or idelalisib failures N = 64 (43 ibrutinib, 21 idelalisib) ORR 70% 12 month PFS 72% One lab TLS

23 Acalabrutinib in R/R CLL First in human phase I/II study N = 62 Median age 62 46% Nodes > 5 cm 67% Rai stage III/IV Median 3 prior therapies (1-13) No prior BCR pathway inhibitors allowed Results Multiple dose levels 100, 175, 250, 400 mg/d 100 BID ORR 95% CR 10% ORR in 17p del 100% N = 18 Byrd et al, NEJM Dec 2015

24 * Adverse events reported in at least 15% of patients, on or before the data cutoff date of October 1, 2015 Includes 1 patient with Grade 5 pneumonia

25 Acalabrutinib ASH Update Abstract #638. Awan et al Acalabrutinib for ibrutinib-intolerant CLL N = 33 ORR 76% Treatment DC in 27% No bleeding. 2 cases of Afib Tolerable for most. Active

26 QUESTIONS?