Ibrutinib- Obinutuzumab Chlorambucil

NEW CHEMOTHERAPY-FREE APPROACHES FOR THE TREATMENT OF LYMPHOID MALIGNANCIES

1 Lymphoma Hub is delivered by Scientific Education Support (SES) CLL – chemotherapy-free regimens: pros and cons

Michael Hallek University Hospital of Cologne Cologne, Germany Disclosures

• Research support: Roche, Gilead, Mundipharma, Janssen, Celgene, Pharmacyclics, Abbvie • Honoraria (speaker’s bureau and/or advisory board): Roche, Gilead, Mundipharma, Janssen, Celgene, Pharmacyclics, Abbvie

3 Novel agents target specific pathways in CLL dasatinib, antigen bosutinib, CXCL12 saracatinib CAL-101 = idelalisib, IPI-145 sIg Ibrutinib MK-2206 CXCR4 CC292

Lyn PIP3 Lyn Btk PI3K G-proteins PLCγ P Akt P Syk P P P Igα/Igβ BLNK P everolimus Bad Ras Bid fosta- mTOR IP DAG Bcl-x matinib 3 Bcl-2 L sorafenib c-Raf P Ca++ PKC Mek Mcl-1 mido- P P P Erk JNK p38 staurine Bak IKK Bax apoptosis NFAT Myc Jun ATF2 NFkB ABT-737, venetoclax, obatoclax, oblimersen Type I CD20 antibodies Type II antibodies • CDC • Low CDC • Low cell death • High cell death • Low aggregation • High aggregation • ADCC • ADCC • Localize to lipid rafts • Do not localize to lipid rafts • FcgRIIB mediated internalization • Half binding capacity • Low FcgRIIB mediated internalization • Rituximab • Ocrelizumab • Ofatumumab

• Ocaratuzumab • GA101 (obinutuzumab) • Veltuzumab malignant B cell • Tositumomab (B1) • Ublituximab Increased efficacy of CLL therapies

100 100 95 90 90 90 85 80 80 Overall response rate (%) 72 70 66 60 Rate of MRD negative remissions (PB) (%) 50 40 40 35 34 30 20 10 10 3 0 0 CLB CLB R CLB G F FC FCR Ven G

CLL8 trial: Overall survival, update 2012 FCR versus FC

1.0 Median observation time 5.9 years 0.8

0.6 FCR 69.4% alive Median not reached FC 62.3% alive

0.4 Median 86 months Cum survival Cum

0.2 HR 0.68, 95% CI 0.535‒0.858 0.0 p=0.001

0 12 24 36 48 60 72 84 96 Time to event [OS] (months) Fischer K, et al. Blood 2012; 120:Abstract 435 (Oral presentation). Hallek M, et al. Lancet 2010; 376:1164‒1174. Survival after FCR chemoimmunotherapy (Fischer et al., Blood 2016)

N (%) Pts 5-year 1.0 alive, OS, % % IGHV 107 85.0 66.6 0.8 mutated patient s* 0.6 +12q 10 (9.3) 100.0 100.0 13q‒ 58 93.1 94.6 (54.2) 0.4 11q‒ 15 93.3 92.9

(14.0) Cum survival Cum Not** 21 57.1 71.4 0.2 (19.6) 17p‒ 3 (2.8) 33.3 33.3

0.0

0 12 24 36 48 60 72 84 96 Time to event [OS] (months) GCLLSG trial Fit or young patients (time of recruitment)

CLL4 FC F (1999-2003) CLL8 FCR FC (2003-2006) CLL10 FCR BR (2008-2011) CLL13 BR/FCR VR VG VIG (2016-2019) ECOG-ACRIN trial Arm A – Ibrutinib + Rituximab Cycles 1: Shanefelt et al., ASH 2018 Ibrutinib 420 mg PO daily, days 1-28 Cycle 2: Cycle 8 until Ibrutinib 420 mg PO daily, days 1-28 progression: Rituximab 50 mg/m2 IV, day 1 Ibrutinib 420 mg PO Rituximab 325 mg/m2 IV, day 2 E1912 daily, days 1-28 Eligibility: Cycles 3-7: -Previously untreated CLL Ibrutinib 420 mg PO daily, days 1-28 2 -Requires treatment (IWCLL 2008) Rituximab 500 mg/m IV, day 1 -Age < 70 -ECOG 0-2 Arm B - FCR -CrCL>40 Cycles 1-6:

-Able to tolerate FCR Fludarabine 25 mg/m2 IV, days 1-3 Randomization

-No deletion 17p by FISH Cyclophosphamide 250 mg/m2 IV, days 1-3 Disease Progression Disease Planned Accrual: 519 Cycle 1: Rituximab 50 mg/m2 IV, day 1, cycle 1 Rituximab 325 mg/m2 IV, day 2, cycle 1 Cycle 2-6: Rituximab 500 mg/m2 IV, day 1, cycles 2-6 Progression Free Survival Intent to Treat Eligible

0 HR = 0.32 (95% CI 0.20-0.51) HRHR = 0.35= 0.35 (95% (95% CI 0.22−0.56) CI 0.22-0.5) HR = 0.32 (95% CI 0.20−0.51) -6 One sided p<0.00001-7

2 One−sidedOne sided p = p<0.000011.62 ´ 10 2 One−sided p = 3.74 ´ 10

0 IR (37 events/ 354 cases) 0 IR (33 events/ 332 cases) FCR (40 events/ 175 cases) FCR (39 events/ 166 cases)

0 1 2 3 4 0 1 2 3 4

Years Years Number at risk Number at risk 354 339 298 148 16 332 321 280 138 16 175 147 112 50 0 166 141 107 47 0

13 Overall Survival

Intent to Treat Eligible

0 0

. .

1 1

8 8

. .

0 0

6 6

. .

y y

0 0

t t

i i

l l

i i

b b

a a

b b

o o

r r

4 4

P P

. .

0 0 HR = 0.17 (95% CI 0.05-0.54) HR = 0.13 (95% CI 0.03-0.46) HR = 0.17 (95% CI 0.05−0.54) HR = 0.13 (95% CI 0.03−0.46) One sided p<0.0003-4 One sided p<0.0001-5

2 One−sided p = 3.22 ´ 10 2 One−sided p = 9.86 ´ 10

. . 0 IR (4 events/ 354 cases) 0 IR (3 events/ 332 cases) FCR (10 events/ 175 cases) FCR (10 events/ 166 cases)

0 0

. .

0 0

0 1 2 3 4 0 1 2 3 4

Years Years Number at risk Number at risk 354 347 318 166 18 332 327 298 154 18 175 155 130 58 1 166 149 125 54 1

14 Alliance North American Intergroup Study A041202, Woyach et al., 2018 (ASH and NEJM)

100

30 Arm N 24 Month Estimate

20 BR 134 79% (95% CI: 71-86%) Arm Events/Total % Alive and Progression-Free and Alive % 10 I 137 88% (95% CI: 81-92%) Arm A (BR) 45/134 Arm B (I) 27/137 IR 132 86% (95% CI: 79-91%) Arm C (IR) 25/132 0 Censor

0 6 12 18 24 30 36 42 48 52 Time (Months) Patients-at-Risk Arm A (BR) 134 113 106 104 87 72 42 21 9 0 Arm B (I) 137 128 120 115 107 95 61 33 14 0 Arm C (IR) 132 120 109 103 100 85 53 31 14 0 15 Overall Survival Intention-to-Treat Patient Population

100

50 Median Follow-up: 38 months % Alive % 40 30 Arm N 24 Month Estimate 20 BR 183 95% (95% CI: 91-98%) Arm Events/Total 10 I 183 90% (95% CI: 85-94%) Arm A (BR) 20/183 Arm B (I) 24/182 Arm C (IR) 22/182 0 IR 182 94% (95% CI: 89-97%) Censor

0 6 12 18 24 30 36 42 48 52 Time (Months) Patients-at-Risk Arm A (BR) 183 166 163 160 153 143 98 53 23 1 Arm B (I) 182 175 166 161 156 146 100 62 26 1 Arm C (IR) 182 172 169 165 161 147 100 55 24 1 16

GCLLSG trial Unfit or older patients (time of recruitment) CLL5 (1999-2004) CLB F

CLL11 (2010-2012) CLB CLB+R CLB+G

CLL14 VG CLB+G (2016-2018) CLL11: Obinutuzumab improves overall survival compared with rituximab (Goede et al., update 2018)

2-yr OS: 91 vs. 84% 5-yr OS: 66 vs 57% Resonate Trial, Overall Survival

Burger et al., NEJM 273 (25): 2425-37, 2016 iLLUMINATE (PCYC-1130) Superior Progression-Free Survival with Ibrutinib-Obinutuzumab

IRC Assessment INV Assessment || 100 | 100 || | | | | | | | | | | | | | | | 90 | | | 90 |

) ) | | | |

% % |

( ( ||| |||

|||| ||||||| ||||

l 80 l 80 ||||| |||| |

i 70 i 70

r ||| r

u u |

60 60

e | e |||

r r |

f 50 f 50

n | n |

i 40 i 40 |

s | s || |||| | | |

s || | s

e |||| | ||| e

r 30 Ibrutinib- Chlorambucil- r 30 Ibrutinib- Chlorambucil-

o o ||

r obinutuzumab obinutuzumab r obinutuzumab obinutuzumab

P 20 P 20 Median (mo) NR 19.0 Median (mo) NR 21.9 10 Hazard ratio 0.231 (0.145–0.367); Ibrutinib-obinutuzumab (N=113) 10 Hazard ratio 0.260 (0.163–0.415); Ibrutinib-obinutuzumab (N=113) (95% CI) P<0.0001 Chlorambucil-obinutuzumab (N=116) (95% CI) P<0.0001 Chlorambucil-obinutuzumab (N=116) 0 0 0 3 6 9 12 15 18 21 24 27 30 33 36 0 3 6 9 12 15 18 21 24 27 30 33 36 Months Months . Median follow-up, 31.3 months (range, 0.2–36.9) . Estimated PFS at 30 months: 79% with ibrutinib-obinutuzumab vs. 31% with chlorambucil-obinutuzumab . Even after excluding patients with del(17p): 74% reduction in risk of progression or death with ibrutinib-obinutuzumab

21 INV, investigator; NR, not reached. ASH 2018, PCYC-1130; Moreno et al. Overall Survival with Median 31 Months of Follow-Up

100 . 46 of 116 patients (40%) 90 randomized to chlorambucil- 80 obinutuzumab crossed over

)

% to receive single-agent

( 70

a ibrutinib

i 60

s 50

a r 40

O 30 Ibrutinib- Chlorambucil- 20 obinutuzumab obinutuzumab Median (mo) NR NR Ibrutinib-obinutuzumab (N=113) 10 Hazard ratio 0.921 (0.479–1.722); (95% CI) P=0.81 Chlorambucil-obinutuzumab (N=116) 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 Months

22 ASH 2018, PCYC-1130; Moreno et al. CLL14 trial: Design Fischer et al., N Engl J Med 2019; 380:2225-2236

Safety Run-in Phase* Venetoclax– Obinutuzumab

Venetoclax– Venetoclax Obinutuzumab Follow-up Phase 6 cycles 6 cycles Previously untreated Primary endpoint: patients with CLL and Progression-free coexisting medical survival 1:1 conditions randomization Key secondary endpoints: CIRS > 6 and/or CrCl < Response, Minimal 70mL/min Residual Disease, Chlorambucil– Chlorambucil Overall Obinutuzumab Survival 6 cycles 6 cycles

* Fischer K et al. Venetoclax and Obinutuzumab in chronic lymphocytic leukemia, Blood 11 May 2017 Progression-free survival Fischer et al. Presidential Symposium Hall 5; 16:45 100 S149

assessed

free survival (%) survival free -

40 Investigator 20 Venetoclax–

Progression Hazard ratio 0.35 (95% CI 0.23 ‒ 0.53), P < 0.0001 Obinutuzumab 28 months median follow-up Chlorambucil– 00 Obinutuzumab 0 6 12 18 24 30 36 Time on study in months MRD levels Over time Fischer et al. Presidential Symposium Hall 5; 16:45 S149 Chlorambucil- Venetoclax-

Obinutuzumab Obinutuzumab MRD Level MRD Level (fraction)

By ASO-PCR in peripheral blood CLL first line treatment (updated June 2019)

del(17p) or Stage Fitness IGVH Therapy p53mut Binet A-B, Rai 0-II, Irrelevant Irrelevant Irrelevant None inactive disease Ibrutinib or Venetoclax + Obinutuzumab or Idelalisib + Yes Irrelevant Irrelevant Rituximab (if contraindications for ibrutinib)*

M FCR (BR above 65 years) or ibrutinib* Go go Active disease or U Ibrutinib or FCR (BR above 65 years)* Binet C or Rai III-IV No Venetoclax + Obinutuzumab or Chlorambucil + M Obinutuzumab or Ibrutinib* Slow go Venetoclax + Obinutuzumab or Ibrutinib or Chlorambucil + U Obinutuzumab*

* Consider and discuss with patient: long-term vs fixed (6-12 m) duration therapy, lack of convincing evidence of overall survival differences, specific side effects of each therapeutic option (myelosuppression, infections, secondary malignancies for CIT; cardiac toxicity, bleeding and autoimmune disease for Ibru; TLS and infections for Ven-Obi; autoimmune disease (diarrhea) and opportunistic infections for Idelalisib). Round table discussion

27 Thank you