Oncology Conference Advances in CLL: Key Elements for Todays - PowerPoint PPT Presentation

2020 Spring Oncology Conference

Advances in CLL: Key Elements for Today’s Clinics

Learning Objectives • Analyze the efficacy and safety of treatment options as well as molecular features of CLL and patient characteristics/preferences to aid in the successful delivery of individualized therapy to patients with newly diagnosed and relapsed/refractory CLL • Consider the optimal treatment for patients with newly diagnosed and relapsed/refractory CLL based on available clinical data, guidelines, and expert recommendations • Develop team-based strategies to address challenges to optimal treatment, including the identification and management of AEs, to ensure treatment compliance as well as improved clinical outcomes and quality of life 3 AE = adverse event; CLL = chronic lymphocytic leukemia.

CLL/SLL: Background • More than 21,000 estimated new cases in 2020 in the United States alone [1] ‒ Most common type of leukemia in adults (37%) • Median age at diagnosis: 70 years [2] • SLL and CLL considered the same B-cell malignancy [3] ‒ CLL: > 5000 clonal B cells in peripheral blood ‒ SLL: presence of lymphadenopathy and/or splenomegaly and < 5000 clonal B cells in peripheral blood • Historical 5-year survival: 66% (range: few mos to normal life span) [4] ‒ Current (2009-2015) 5-year survival: 85% [2] SLL = small lymphocytic lymphoma. 4 1. Siegel. CA Cancer J Clin. 2020;70:7. 2. SEER Cancer Stat Facts. Chronic lymphocytic leukemia. 4 3. American Cancer Society. Chronic lymphocytic leukemia. 4. Nabhan. JAMA. 2014;312:2265.

CLL: Prognostic Value of FISH Probability of OS From Diagnosis, by Genetic Aberration FISH Abnormalities Present in 268/325 Patients (82%) 100 17p deletion 11q deletion Lesion % Median OS, Mos 12q trisomy del(13q) 55 133 Normal 80 13q deletion as del(11q) 18 79 Patients Surviving (%) sole abnormality Trisomy 12 16 114 60 del(17p) 7 32 del(6q) 6 N/A Normal 18 111 40 FISH Patients With Abnormality (%) Lesion Dohner et al Oscier et al Jarosova et Dewald et Sindelarava 20 1997 1999 al 2001 al 2003 et al 2005 del(13q) 45 36 18 47 54 Trisomy 12 15 15 13 25 16 0 del(17p) 10 8 11 8 16 Months del(11q) 20 17 11 15 12 Dohner. NEJM. 2000;343:1910. Dohner. Leukemia. 1997;11(suppl 2):S19. Oscier. Haematologica. 1999;84(suppl EHA-4):88. 5 Jarosova. Onkologie. 2001;24:60. Dewald. Br J Haematol. 2003;121:287. Sindelárová. Cancer Genet Cytogenet. 2005;160:27.

CLL: Impact of TP53 Mutations and TP53 Deletion on OS (N = 1148) • OS effect of TP53 wild type: ‒ vs TP53 mut only: P = .013 ‒ vs TP53 del only: P = .006 ‒ vs TP53 mut + del: P < .001 Relation to Total Size of Each Cohort 9 100 100 Frequency of TP53 Alterations in TP53 mut only TP53 wt 8 TP53 del only TP53 wt TP53 mut + del 80 80 7 6 60 60 OS (%) OS (%) TP53 mut only 5 (%) 4 40 40 TP53 alteration TP53 del only 3 2 20 20 TP53 mut + del 1 P < .001 0 0 0 0 1 2 3 4 5 6 7 8 9 10 0 1 2 3 4 5 6 7 8 9 10 CLL Years Years • Analysis based on cases referred to the Munich Leukemia Laboratory between August 2005 and May 2013 6 Stengel. Leukemia. 2017;31:705.

Survival in CLL According to IGHV Mutational Status All Patients (n = 84) Binet Stage A Patients (n = 62) 100 100 80 80 Mutated Surviving (%) Surviving (%) Mutated 60 60 40 40 Unmutated 20 20 Unmutated P = .0008 P = .001 0 0 0 50 100 150 200 250 300 0 50 100 150 200 250 300 Months Months 7 Hamblin. Blood. 1999;94:1848.

Previously Untreated CLL

Case Study 1: An Elderly Patient With del(17p) and a TP53 Mutation • 75-year-old female patient who presented in 2013 with WBC 13K, ALC 9, Hgb 13, PLTs 160K • Flow: typical CLL pattern • FISH: no mutations • She was observed for 5 years • In 2018, progressive weight loss, splenomegaly, bulky lymphadenopathy, WBC 310K, Hgb 9 ‒ IGHV unmutated, TP53 mutation ‒ FISH: del(17p) 9

Phase III RESONATE-2: Ibrutinib vs Chlorambucil in Patients 65 Years of Age or Older With Untreated CLL/SLL • An international, randomized phase III trial Ibrutinib 420 mg/day until PD or unacceptable toxicity (n = 136) Patients 65 years of age Crossover or older with treatment- upon PD (n = 43) naive CLL/SLL; no Chlorambucil del(17p); no warfarin use 0.5 mg/kg (up to maximum of 0.8 mg/kg) (N = 269) on Days 1, 15 of 28-day cycle for up to 12 cycles (n = 133) • Primary endpoint: PFS • Secondary endpoints: OS, ORR, EFS, rate of hematologic improvement, and safety 10 10 Burger. NEJM. 2015;373:2425.

RESONATE-2: 5-Year Follow-up Results 100 100 Ibrutinib 80 80 Ibrutinib Chlorambucil 60 Ibrutinib Chlorambucil OS (%) 60 PFS (%) (n = 136) (n = 133) mPFS, mos NE 15 HR (95% CI) 0.146 (0.098-0.218) 40 40 Ibrutinib Chlorambucil 5-year PFS rate, % 70 12 mOS, mos NE NE HR (95% CI) 0.450 (0.266-0.761) Chlorambucil 20 20 5-year OS rate, % 83 68 0 0 0 3 6 9 1215 18 2124 27303336 394245 48 5154 57 6063 66 69 0 3 6 9 12 15 18 21 24 27 30 3336 39 42 45 48 51 54 57 60 63 66 69 Months Months • Ibrutinib was generally well tolerated with no new safety signals reported with long-term follow-up (many AEs decreased over time) • More than one half (58%) of patients remained on ibrutinib at the 5-year follow-up 11 Burger. Leukemia. 2020;34:787.

Phase III E1912 Trial of Ibrutinib + Rituximab vs FCR in Patients ≤ 70 Years of Age With Previously Untreated CLL • Primary analysis of randomized, open-label phase III trial (data cutoff: October 24, 2018) Stratified by age (< vs ≥ 60 yrs), ECOG PS (0/1 vs 2), stage (III-IV vs I-II), del(11q22.3) vs other Ibrutinib 420 mg PO daily for cycles 1-7 + Rituximab 50 mg/m 2 IV on Day 1, cycle 2, then 325 mg/mg 2 on Ibrutinib maintenance Patients with previously untreated CLL Day 2, cycle 2, then 500 mg/m 2 on Day 1, cycles 3-7 requiring treatment per IWCLL 2008, ≤ until PD (n = 354) 70 years of age, ECOG PS 0-2, CrCl > 40 mL/min, ability to tolerate FCR, no Fludarabine 25 mg/m 2 IV on Days 1-3 for cycles 1-6 + del(17p) by FISH Cyclophosphamide 250 mg/m 2 IV on Days 1-3 for cycles 1-6 + (N = 529) Rituximab 50 mg/m 2 IV on Day 1, cycle 1, then 325 mg/mg 2 on Day 2, cycle 1, then 500 mg/m 2 on Day 1, cycles 2-6 (n = 175) 28-day cycles • Primary endpoint: PFS ⎻ Study has 80% power to detect PFS HR for IR vs FCR of 0.67 using stratified log-rank test, with prespecified boundary of 2.87 for first PFS interim analysis corresponding to 1-sided P = .0025 • Secondary endpoints: OS, safety 12 12 Shanafelt. NEJM. 2019;381:432. Shanafelt. ASH 2019. Abstr 33.

E1912: PFS (Primary Endpoint) Median follow-up: 48 months 1.0 Ibrutinib + rituximab (58 events/354 cases) 0.8 FCR (52 events/175 cases) Probability 0.6 0.4 0.2 HR: 0.39 (95% CI: 0.26-0.57) P < .0001 3-year rates: 89%, 71% 0 0 1 2 3 4 5 Years Number at risk FCR 175 145 123 82 31 0 Ibrutinib + R 354 338 321 280 121 8 13 Shanafelt. ASH 2019. Abstr 33.

E1912: PFS by IGHV Status Median follow-up: 48 months IGHV Mutated IGHV Unmutated 1.0 1.0 Ibrutinib + rituximab (10 events/70 cases) 0.8 0.8 Ibrutinib + rituximab FCR (8 events/44 cases) (36 events/210 cases) FCR (29 events/71 cases) Probability Probability 0.6 0.6 0.4 0.4 0.2 0.2 HR: 0.42 (95% CI: 0.16-1.16) HR: 0.28 (95% CI: 0.17-0.48) P = .086 P < .0001 3-year rates: 88%, 82% 3-year rates: 89%, 65% 0 0 0 1 2 3 4 5 0 1 2 3 4 5 Years Years Number at risk Number at risk FCR 71 63 50 31 8 0 FCR 44 38 34 25 11 0 Ibrutinib + R 210 202 193 165 72 7 Ibrut + R 70 67 64 54 20 1 14 Shanafelt. ASH 2019. Abstr 33.

E1912: OS Median follow-up: 48 months Ibrutinib + rituximab (11 events/354 cases) 1.0 FCR (12 events/175 cases) 0.8 Probability 0.6 0.4 0.2 HR: 0.34 (95% CI: 0.15-0.79) P = .009 3-year rates: 99%, 93% 0 0 1 2 3 4 5 Years Number at risk FCR 175 155 143 131 69 9 Ibrutinib + R 354 347 343 355 193 37 15 Shanafelt. ASH 2019. Abstr 33.

First-line Ibrutinib vs Ibrutinib + Rituximab vs Bendamustine + Rituximab in CLL/SLL (A041202): Study Design • Multicenter, randomized, double-blind phase III study (data cutoff: October 4, 2018) Stratified by Rai stage (high vs intermediate risk), del(11q22.3) or del(17p13.1) (presence vs absence), ZAP- 70 methylation (< vs ≥ 20%) Ibrutinib 420 mg daily Until PD (n = 182) Untreated patients with CLL meeting IWCLL 2008 criteria for tx initiation; ≥ 65 years of age; ECOG Ibrutinib 420 mg daily + PS 0- 2; ANC ≥ 1000 unless due to Rituximab 375 mg/m 2 weekly x 4 weeks starting cycle 2 Day 1; cycles 3-6 Day 1* Ibrutinib until PD BM involvement; PLT ≥ 30; (n = 182) CrCl CG ≥ 40; AST/ALT ≤ 2.5 x ULN; Crossover to no heparin or warfarin Bendamustine 90 mg/m 2 on Days 1, 2 + ibrutinib within (N = 547) Rituximab 375 mg/m 2 on cycle 1 Day 1; 500 mg/m 2 on cycles 2-6 Day 1* 1 year of PD (n = 183) allowed *28-day cycles. • Primary endpoint: PFS ‒ 2 primary comparisons of ibrutinib vs BR and ibrutinib + R vs BR with 90% power to detect HR of 0.586 (estimated 2-yr PFS rates: ibrutinib, 75%; BR, 61%) and overall 1-sided α = 0.025 for each comparison ‒ If both primary comparisons significant, third planned comparison of ibrutinib + R vs ibrutinib 16 Woyach. NEJM. 2018;379:2517.