BR is an established treatment regimen for CLL in the front-line and R/R settings

Transcription

1 Idelalisib plus bendamustine and rituximab (BR) is superior to BR alone in patients with relapsed/refractory CLL: Results of a phase III randomized double-blind placebo-controlled study Andrew D. Zelenetz, Tadeusz Robak, Bertrand Coiffier, Julio Delgado, Paula Mariton, Adeboye H. Adewoye, Yeonhee Kim, Lyndah K. Dreiling, Peter Hillmen ASH Annual Meeting Abstracts 2015:LBA-5

2 Background CLL typically progresses after initial therapy, which necessitates retreatment Durable treatment responses are more difficult to achieve with each relapse BR is an established treatment regimen for CLL in the front-line and R/R settings Signalling via PI3K is hyperactive in CLL; inhibition of PI3Kδ impacts multiple critical pathways in B-cells Idelalisib, a first-in-class PI3Kδ inhibitor, has demonstrated efficacy and is approved for the treatment of R/R CLL It is hypothesized that idelalisib in combination with BR would improve PFS and would be tolerable in the study population BR = bendamustine plus rituximab; CLL = chronic lymphocytic leukemia; PFS = progression-free survival; PI3K = phosphatidylinositol 3-kinase; R/R = relapsed/refractory

3 Study Design Enrolment period: June 2012 August 2014 Imaging by CT or MRI was performed at baseline and at every 12 weeks, or at PD Pre-specified interim analysis was performed at 67% of the total number of planned events of CLL progression Stratification was based on the presence of del(17p) and/or TP53 mutation, IGHV mutation status, and disease status (refractory vs. relapsed CLL) Primary endpoint: PFS Secondary endpoints: ORR, nodal response, OS, and CR B = bendamustine; bid = twice daily; C = cycle; CLL = chronic lymphocytic leukemia; CR = complete response; CT = computerized tomography; D = day; del(17p) = deletion 17p; IGHV = immunoglobulin heavy chain variant; MRI = magnetic resonance imaging; ORR = overall response rate; OS = overall survival; PD = disease progression; PFS = progression-free survival; R = rituximab; TP53 = tumour protein 53

4 Key Eligibility Criteria CLL progression within 36 months from the last prior therapy, requiring treatment Measurable disease No history of transformation of CLL No progression within six months from the last bendamustine treatment No prior treatments with inhibitors of BTK, PI3Kδ, and SYK BTK = Bruton s tyrosine kinase; CLL = chronic lymphocytic leukemia; PI3Kδ = phosphatidylinositol 3-kinase delta; SYK = spleen tyrosine kinase

5 Patient Disposition Randomized, n = 416 Treated with idelalisib + BR n = 207 Discontinued study, n = 52 AEs (n = 24) Physician decision (n = 6) Withdrew consent (n = 14) Other (n = 8) Treated with placebo + BR n = 209 Discontinued study, n = 41 AEs (n = 11) Physician decision (n = 18) Withdrew consent (n = 7) Other (n = 5) Off study due to PD or death n = 40 (19%) Ongoing on study n = 115 (56%) Ongoing on study n = 63 (30%) Off study due to PD or death n = 105 (50%) On treatment n = 109 (52%) On treatment n = 60 (29%) Patient disposition is based on investigator assessment. AE = adverse event; BR = bendamustine plus rituximab; PD = disease progression

6 Baseline Characteristics Idelalisib + BR (n = 207) Placebo + BR (n = 209) Median age, years (range) 62 (38 83) 64 (32 82) Male, % White race, % Median time since diagnosis, months Rai stage, 0 / I II/ III IV, % 1 / 48 / 50 2 / 53 / 42 Median number of prior regimens (range) 2 (1 13) 2 (1 10) Baseline cytopenias, any / Grade 3/4, % Most common prior regimens, % Anemia Neutropenia Thrombocytopenia FCR FC Chlorambucil BR Rituximab R-CVP 53 / 3 23 / 7 59 / / 1 23 / 8 55 / BR = bendamustine plus rituximab; FC = fludarabine plus cyclophosphamide; FCR = fludarabine, cyclophosphamide, and rituximab; R-CVP = rituximab, cyclophosphyamide, vincristine, and prednisone

7 Patient Distribution by Stratification Factors Idelalisib + BR (n = 207), % Placebo + BR (n = 209), % Del(17p) and/or TP53 Either Neither IGHV mutation status Yes No Disease status Refractory Relapsed BR = bendamustine plus rituximab; del(17p) = deletion 17p; IGHV = immunoglobulin heavy chain variant; TP53 = tumour protein 53

8 IRC-Assessed PFS

9 PFS by Subgroups

10 Response Rates Response parameter Idelalisib + BR (n = 207), % (95% CI) Placebo + BR (n = 209), % (95% CI) Overall response 68 (61 74) 45 (38 52) CR 5 (2) 0 50% reduction in lymph nodes 96 (93 99) 61 (54 68) Organomegaly response Spleen 82 (75 88) 57 (49 65) Liver 56 (46 66) 40 (31 50) Hematologic response Hemoglobin 88 (78 95) 70 (58 80) Neutrophils 89 (71 98) 84 (67 95) Platelets 89 (80 95) 78 (66 87) BR = bendamustine plus rituximab; CI = confidence interval; CR = complete response

11 Nodal Response

12 Overall Survival

13 Overall Survival in Patient Subgroups

14 Summary of AEs Events, n (%) Idelalisib + BR (n = 207) Placebo + BR (n = 209) Any AE 207 (100) 203 (97) Grade (93) 159 (76) Any SAE 137 (66) 92 (44) AE leading to dose reduction 22 (11) 13 (6) AE leading to drug discontinuation 54 (26) 28 (13) Death 21 (10) 15 (7) AE = adverse event; BR = bendamustine plus rituximab; SAE = serious adverse event

15 AEs (>10% of Patients) Idelalisib + BR (n = 207) Placebo + BR (n = 209) AE, n (%) Any grade Grade 3 Any grade Grade 3 Neutropenia 131 (63) 124 (60) 112 (54) 96 (46) Pyrexia 86 (42) 14 (7) 63 (30) 7 (3) Diarrhea 73 (35) 15 (7) 45 (22) 4 (2) Nausea 56 (27) 2 (1) 72 (34) 2 (1) Anemia 53 (26) 30 (15) 47 (23) 25 (12) Thrombocytopenia 46 (22) 27 (13) 49 (23) 24 (12) Febrile neutropenia 45 (22) 42 (20) 14 (7) 12 (6) Cough 44 (21) 1 (<1) 46 (22) 2 (1) Fatigue 42 (20) 7 (3) 52 (25) 5 (2) Pneumonia 36 (17) 23 (11) 23 (11) 13 (6) Rash 33 (16) 6 (3) 25 (12) 0 AE = adverse event; BR = bendamustine plus rituximab

16 AEs (>10% of Patients), cont d AE, n (%) Idelalisib + BR (n = 207) Placebo + BR (n = 209) Any grade Grade 3 Any grade Grade 3 Vomiting 32 (16) 2 (1) 30 (14) 2 (1) Constipation 32 (16) 1 (<1) 35 (17) 0 ALT increased 31 (15) 22 (11) 3 (1) 1 (<1) Infusion-related reaction 30 (15) 5 (2) 48 (23) 4 (2) Upper respiratory tract infection 28 (14) 2 (1) 23 (11) 3 (1) Arthralgia 25 (12) 2 (1) 16 (8) 0 Chills 23 (11) 0 14 (7) 0 Dyspnea 22 (11) 5 (2) 28 (13) 9 (4) Asthenia 22 (11) 1 (<1) 20 (10) 5 (2) Decreased appetite 20 (10) 4 (2) 15 (7) 0 Headache 20 (10) 1 (<1) 22 (11) 1 (<1) AE = adverse event; ALT = alanine aminotransferase; BR = bendamustine plus rituximab

17 SAEs (>2% of Patients) SAE, n (%) Idelalisib + BR (n = 207) Placebo + BR (n = 209) Febrile neutropenia 37 (18) 10 (5) Pneumonia 28 (14) 13 (6) Pyrexia 24 (12) 12 (6) Neutropenia 9 (4) 3 (1) Sepsis 9 (4) 3 (1) Anemia 5 (2) 5 (2) Lower respiratory tract infection 5 (2) 5 (2) Diarrhea 8 (4) 1 (<1) Neutropenic sepsis 3 (1) 6 (3) Urinary tract infection 5 (2) 3 (1) Respiratory tract infection 2 (1) 5 (2) Bronchitis 1 (<1) 5 (2) Septic shock 5 (2) 1 (<1) Squamous cell carcinoma 1 (<1) 5 (2) BR = bendamustine plus rituximab; SAE = serous adverse event

18 Laboratory Abnormalities Laboratory abnormality, n (%) Idelalisib + BR (n = 207) Placebo + BR (n = 209) Any grade Grade 3 Any grade Grade 3 ALT elevation 124 (60) 44 (21) 64 (31) 6 (3) AST elevation 108 (52) 32 (16) 58 (28) 7 (3) Anemia 120 (58) 40 (19) 126 (60) 31 (15) Neutropenia 186 (90) 150 (73) 187 (90) 131 (63) Thrombocytopenia 102 (49) 41 (20) 109 (52) 33 (16) ALT = alanine aminotransferase; AST = aspartate aminotransferase; BR = bendamustine plus rituximab

19 Summary and Conclusion The combination of idelalisib plus BR was superior to BR alone in patients with R/R CLL The efficacy results were consistent across patients with or without high-risk features, such as del(17p)/tp53 mutations, unmutated IGHV, and refractory disease The safety profile was consistent with previously reported studies Idelalisib plus BR represents an important new option for patients with R/R CLL BR = bendamustine plus rituximab; CLL = chronic lymphocytic leukemia; del(17p) = deletion 17p; IGHV = immunoglobulin heavy chain variant; R/R = relapsed/refractory; TP53 = tumour protein 53