updated efficacy and safety from the phase 3 resonate-2 ™ study: ibrutinib as first ... · 2017....

Updated Efficacy and Safety From the Phase 3 RESONATE-2 ™ Study: Ibrutinib as First-Line Treatment

Option in Patients 65 Years and Older With Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Paul Barr, MD1, Tadeusz Robak, MD2, Carolyn Owen, MD3, Alessandra Tedeschi, MD4, Osnat Bairey, MD5, Nancy Bartlett, MD6, Jan Burger, MD, PhD7, Peter Hillmen,

MBChB, PhD8, Steven Coutre, MD9, Stephen Devereux, PhD, FRCP, FRCPath10, Sebastian Grosicki, MD, PhD11, Helen McCarthy, MBBS, PhD12, Jianyong Li, MD13, David Simpson, MBChB, FRACP, FRCPA14, Fritz Offner, MD15, Carol Moreno, MD16, Cathy Zhou, MS17, Lori Styles, MD17, Danelle James, MD, MAS17, Thomas J. Kipps,

MD, PhD18, and Paolo Ghia, MD, PhD19

1University of Rochester, Rochester, NY; 2Medical University of Lodz, Poland; 3Tom Baker Cancer Centre, Calgary, Canada; 4Niguarda Ca’ Granda Hospital, Milan, Italy; 5Rabin Medical Center, Beilinson Campus, Petah Tikvah, Israel;

6Washington University School of Medicine, St. Louis, MO; 7University of Texas MD Anderson Cancer Center, Houston, TX; 8The Leeds Teaching Hospitals, St. James Institute of Oncology, Leeds, UK; 9Stanford University School of Medicine, Stanford, CA; 10Kings College Hospital, NHS Foundation Trust, London, UK; 11School of Public Health, Silesian Medical University, Katowice, Poland; 12Royal Bournemouth Hospital, Bournemouth, UK; 13Jiangsu Province Hospital, Nanjing, China; 14North Shore Hospital, Auckland, New Zealand; 15Universitair Ziekenhuis Gent, Gent, Belgium; 16Hospital de la

Santa Creu i Sant Pau, Barcelona, Spain; 17Pharmacyclics, LLC, an AbbVie Company, Sunnyvale, CA; 18University of California, San Diego, Moores Cancer Center, La Jolla, CA; 19Università Vita-Salute San Raffaele and IRCCS Istituto

Scientifico San Raffaele, Milan, Italy.

ASH 2016, Updated Efficacy/Safety RESONATE-2; Barr et al.

CLL: older population with frequent comorbidities1

– Fludarabine-based regimens unsuitable for frail or older patients2

– Chlorambucil: has been a standard first-line therapy in older patients

Ibrutinib: first-in-class, oral, covalent BTK inhibitor

– Approved by FDA and EMEA for CLL and allows for treatment without chemotherapy in all lines of therapy

Phase 2 PCYC-1102/1103 study: treatment-naïve (TN) CLL3

– With extended treatment (median 46 mo), complete response (CR) rate has increased (29%) with 65% of patients continuing on therapy.

Phase 3 PCYC-1115 (RESONATE-2™): ibrutinib in treatment-naïve (TN) CLL/SLL patients ≥65 years of age4,5

– Superior PFS, OS, ORR, and hematologic improvement, and a tolerable safety profile of ibrutinib vs. chlorambucil

– 84% reduction in the risk of death at median follow-up of 18.4 months

Current analysis is with median follow-up of 29 months

Background

CLL, chronic lymphocytic leukemia; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; SLL, small lymphocytic lymphoma.1. Thurmes et al. Leuk Lymphoma. 2008;49:49-56; 2. Eichhorst et al. Blood. 2009; 114:3382-3391; 3. O’Brien et al. ASH 2016; Abstract 233; 4. Burger et al. N Engl J Med. 2015; 373:2425-2437; 5. Tedeschi et al. ASH 2015; Abstract 495.


RESONATE-2 (PCYC-1115/1116) Study Design

Patients (N=269)• Treatment-naïve

CLL/SLL with active disease

• Age ≥65 years• For patients 65-69

years, comorbidity that may preclude FCR

• del17p excluded

ibrutinib 420 mg once daily until

progression

chlorambucil 0.5 mg/kg (to maximum 0.8 mg/kg) days 1 and 15 of 28-day

cycle up to 12 cycles

CLL progression

or 1115 study

closure

PCYC-1116Extension

Study*

In clb arm, n=55

crossed over to ibrutinib

following PD

Stratification factors• ECOG status (0-1 vs. 2)• Rai stage (III-IV vs. ≤II)

RANDOMIZE

1:1

Efficacy (PFS, OS, ORR) determined by investigator-assessment.

*Patients could enroll in separate extension study PCYC-1116 after independent review committee-confirmed PD or at study PCYC-1115 closure for continuing treatment and follow-up.


Patient Characteristics

Characteristicibrutinib(n=136)

chlorambucil(n=133)

Median age, years (range)≥70 years, %

73 (65–89)71

72 (65–90)70

ECOG performance status, %12

488

509

Rai stage III or IV, % 44 47

CIRS score >6, % 31 33

Creatinine clearance <60 mL/min, % 44 50

Bulky disease ≥5 cm, % 40 30

β2-microglobulin >3.5 mg/L, % 63 67

Hemoglobin ≤11 g/dL, % 38 41

Platelet count ≤100 x 109/L, % 26 21

Del11q, % 21 19

Unmutated IGHV, % 43 45


Ibrutinib Prolonged PFS Over Chlorambucil

88% reduction in the risk of progression or death for patients randomized to ibrutinib Subgroup analysis of PFS revealed benefit was observed across all sub-groups

(n=136)

(n=133)

Median PFS not reached

Median PFS 15 mo


Ibrutinib Significantly Improved PFS in Patients with Del11q

Ibrutinib led to 99% reduction in risk of progression or death in high-risk del11q subgroup and 82% reduction in those without del11q, compared to chemotherapy

(n=101)

(n=29)

(n=96)

(n=25)

(n=101)

(n=29)

(n=96)

(n=25)

ibrutinibdel11q yes (n=29)

del11q no (n=101)

del11q yes (n=25)

chlorambucil del11q no (n=96)


Ibrutinib Significantly Improved PFS in Patients Regardless of IGHV Status

Ibrutinib led to 83% and 92% reduction in the risk of progression or death in patients with mutated and unmutated IGHV, respectively, compared to chemotherapy

(n=40)

(n=58)

(n=42)

(n=60)


Ibrutinib Continues to Demonstrate OS Benefit Over Chlorambucil With Longer Follow-Up and Cross-Over

(n=136)

(n=133)


ORR in the Ibrutinib* Arm

Ibrutinib CR rates continue to improve over time: increasing from 7% at 12 months to 15% at 24 months to 18% with median follow-up of 29 months.

CR, complete response; CRi, CR with incomplete blood count recovery.

71%86%

67% 74%65%

18%

14%

20%21%

20%

0%10%20%30%40%50%60%70%80%90%

100%

All Patients(N=136)

With Del11q(n=29)

WithoutDel11q (n=101)

UnmutatedIGHV (n=58)

Mutated IGHV(n=40)

PR-L PR nPR CR/CRi

1%

1%

1%

2%

3%

95%88%

100%92% 90%

0

6070

9080

100

40302010

50

Be

st R

esp

on

se (

%)

*Response rates with chlorambucil are the same as in the original report (Burger NEJM 2015)


Improvement in Hematologic Function

Sustained improvement in hemoglobin in patients with anemia: 90% with ibrutinib vs. 45% with chlorambucil (P<0.0001)

Sustained improvement in platelet counts in patients with thrombocytopenia: 80% with ibrutinib vs. 46% with chlorambucil (P=0.0055)

Hemoglobin Over Time Platelet Count Over Time


Most Patients Remain on Ibrutinib Treatment

First-line ibrutinib (n=135)

Median duration of ibrutinib treatment, mo (range)

29 (1-36)

Treatment duration, n (%)≤12 months>12-24 months>24-36 months

14 (10)9 (7)

112 (83)

Continuing ibrutinib on study, n (%) 107 (79)

Discontinued ibrutinib, n (%)Disease ProgressionAEsDeathWithdrawal of consentInvestigator decision

28 (21)4 (3)

16 (12)6 (4)2 (1)

0

79% of patients continue on ibrutinib treatment on study with 83% of patients receiving at least 2 years of treatment


Most Frequent AEs in Ibrutinib Arm

Additional AEs of clinical interest

– Major hemorrhage occurred in 7% of ibrutinib-treated patients (1 Grade 2, 7 Grade 3, 1 Grade 4; 5 in first 12 months and 4 between 1-2 years)

– Atrial fibrillation occurred in 10% of ibrutinib-treated patients (1 Grade 1, 7 Grade 2, 6 Grade 3)

Ibrutinib Arm (n=135)

Adverse Event, %Grade

1Grade

2Grade

3Grade

4Grade

5Any

Grade

Diarrhea 30 12 4 0 0 45

Fatigue 22 10 2 0 0 33

Cough 22 6 0 0 0 28

Anemia 6 10 6 1 0 23

Nausea 16 7 1 0 0 23

Peripheral edema 15 5 1 0 0 21

Arthralgia 11 7 2 0 0 20

Pyrexia 13 7 1 0 1 20

AE, adverse event.


Treatment-Emergent AEs (≥Grade 3) Over Time in First-Line Ibrutinib Patients (≥4% Over 29 Months Median Follow-Up)

Grade ≥3 AEs in ≥4% of patients over the 29 mo follow-up: neutropenia (12%), pneumonia (7%), anemia (7%), hypertension (5%), hyponatremia (4%), and atrial fibrillation (4%)

Most Grade ≥3 AEs in ibrutinib-treated patients decreased over time

Ibrutinib Arm

0-≤12 months (n=135), %

>12-24 months (n=123), %

>24-36 months(n=112), %

Neutropenia 8 4 0

Pneumonia* 5 2 1

Anemia 6 1 1

Hypertension 4 2 0

Hyponatremia 2 2 0

Atrial fibrillation 1 0 4

*No PCP/PJP occurred.


Dose Reduction and Discontinuation Rates Decrease Over Time for First-Line Ibrutinib

0

2

4

6

8

10

12

≤12(n=135)

>12-24(n=121)

>24-36(n=112)

Pat

ien

ts, %

Months

Dose reduction

Discontinuation due to AE

AEs in ≥2 patients leading to discontinuation of ibrutinib: hemorrhage (3), infection (3), atrial fibrillation (2), and rash (2).


Outcomes Following First-Line Ibrutinib Discontinuation

Of 7 patients who received subsequent therapy (FCR [n=3], BR [n=2], chlorambucil [n=1], radiation [n=1], 6 (86%) remained alive with median 21 (range: 9-25) months follow-up.

Current data reflects that 2 BR patients achieved a PR, 1 FCR and 1 chlorambucil achieved a PR. The other 2 FCR patients did not continue into the extension study so their response information is not available

Patients evaluated for outcomes

Discontinued due to AE

(n=16)

Discontinued due to PD(n=4)

Discontinued due to any cause

(n=22)

Median follow-up, mo 13 10 13

Median OS, mo NR NR NR

Remain alive, n (%) 13 (81) 2 (50) 16 (73)

BR, bendamustine + rituximab; FCR, fludarabine + cyclophosphamide + rituximab.


With a median time on study of 29 months, ibrutinib continued to have substantial efficacy, with 88% reduction in risk of progression or death compared to chlorambucil

– 24-mo PFS: 89% vs 24%

– 24-mo OS: 95% vs 84%, reflects 55 patients who crossed over to ibrutinib

Within the ibrutinib arm, robust outcomes were observed for those with del11q or unmutated IGHV

– In the chlorambucil arm patients with del11q or unmutated IGHV experiencedinferior outcomes

The quality of responses has improved over time, with 18% of CLL/SLL patients achieving a CR/CRi with single agent ibrutinib

Rates of treatment-limiting AEs, including dose reductions and discontinuations, decreased over time, with 79% of this elderly patient population continuing daily ibrutinib

Conclusions


We thank the patients who participated in the study and their supportive families as well as the investigators and clinical research staff from the study centers. This study was sponsored by Pharmacyclics, LLC, an AbbVie Company. Editorial support was provided by Stacey Rose, PhD, funded by Pharmacyclics, LLC, an AbbVie Company.

Acknowledgements


PFS by Subgroup Analysis


Overall Survival Adjusted for Crossover

Cox Model

Log Rank P valueHazard Ratio 95% CI

Excluding crossover patientsa 0.310 0.146-0.657 0.0013

RPSFT modelb 0.280 0.130-0.604 -

RPSFT, rank-preserving structural failure time.aAnalysis stratified by 2 randomization factors: ECOG PS (0-1 vs 2) and Rai stage (0/I/II vs III/IV) at baseline as reported in the interactive web response system. bCox model including treatment and baseline covariates to compensate for any lack of balance between treatment arms and improve precision (ECOG PS, Rai stage, age, sex, bulky disease, del11q, region, ethnicity, lactate dehydrogenase, β2-microglobulin, creatinine clearance).

updated efficacy and safety from the phase 3 resonate-2 ™ study: ibrutinib as first ... · 2017....

Documents