Rutin 1541

Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors, ATC code: L01EL02. Mechanism of action Acalabrutinib is a selective inhibitor of Bruton tyrosine kinase (BTK).‍‍‍‍‍‍​​​‍​​​​​​ BTK is a signalling molecule of the B‑cell antigen receptor (BCR) and cytokine receptor pathways. In B‑cells, BTK signalling results in B‑cell survival and proliferation, and is required for cellular adhesion, trafficking, and chemotaxis. Acalabrutinib and its active metabolite, ACP‑5862, form a covalent bond with a cysteine residue in the BTK active site, leading to irreversible inactivation of BTK with minimal off‑target interactions. Pharmacodynamic effects In patients with B‑cell malignancies dosed with acalabrutinib 100 mg twice daily, median steady‑state BTK occupancy of ≥ 95% in peripheral blood was maintained over 12 hours, resulting in inactivation of BTK throughout the recommended dosing interval. Cardiac electrophysiology The effect of acalabrutinib on the QTc interval was evaluated in 46 healthy male and female subjects in a randomised, double‑blind thorough QT study with placebo and positive controls. At a supratherapeutic dose, 4‑times the maximum recommended dose, Calquence did not prolong the QT/QTc interval to any clinically relevant extent (e.g., not greater than or equal to 10 ms) (see sections 4.4, 4.8 and 5.3). Clinical efficacy and safety Patients with previously untreated CLL Calquence monotherapy or in combination with obinutuzumab The safety and efficacy of Calquence monotherapy or in combination with obinutuzumab in previously untreated CLL were evaluated in a randomised, multi‑centre, open‑label Phase 3 study (ELEVATE‑TN) of 535 patients. Patients received Calquence plus obinutuzumab, Calquence monotherapy, or obinutuzumab plus chlorambucil. Patients 65 years of age or older, or between 18 and 65 years of age with coexisting medical conditions, were included in ELEVATE‑TN, 27.9% patients had a CrCl of < 60 mL/min. Of the patients who were < 65 years of age, 16.1% had a median CIRS‑G score of 8. The study allowed patients to receive antithrombotic agents. Patients who required anticoagulation with warfarin or equivalent vitamin K antagonists were excluded. Patients were randomised in a 1:1:1 ratio into 3 arms to receive • Calquence plus obinutuzumab (Calquence+G): Calquence 100 mg was administered twice daily starting on Cycle 1 Day 1 until disease progression or unacceptable toxicity. Obinutuzumab was administered starting on Cycle 2 Day 1 for a maximum of 6 treatment cycles. Obinutuzumab 1 000 mg was administered on Days 1 and 2 (100 mg on Day 1 and 900 mg on Day 2), 8 and 15 of Cycle 2 followed by 1 000 mg on Day 1 of Cycles 3 up to 7. Each cycle was 28 days. • Calquence monotherapy: Calquence 100 mg was administered twice daily until disease progression or unacceptable toxicity. • Obinutuzumab plus chlorambucil (GClb): Obinutuzumab and chlorambucil were administered for a maximum of 6 treatment cycles. Obinutuzumab 1 000 mg was administered on Days 1 and 2 (100 mg on Day 1 and 900 mg on Day 2), 8 and 15 of Cycle 1 followed by 1 000 mg on Day 1 of Cycles 2 up to 6. Chlorambucil 0.5 mg/kg was administered on Days 1 and 15 of Cycles 1 up to 6. Each cycle was 28 days. Patients were stratified by 17p deletion mutation status (presence versus absence), ECOG performance status (0 or 1 versus 2) and geographic region (North America and Western Europe versus Other). After confirmed disease progression, 45 patients randomised on the GClb arm crossed over to Calquence monotherapy. Table 6 summarises the baseline demographics and disease characteristics of the study population. Table 6. Baseline patient characteristics in (ELEVATE‑TN) patients with previously untreated CLL Characteristic Calquence plus obinutuzumab N=179 Calquence monotherapy N=179 Obinutuzumab plus chlorambucil N=177 Age, years; median (range) 70 (41-88) 70 (44-87) 71 (46-91) Male; % 62 62 59.9 Caucasian; % 91.6 95 93.2 ECOG performance status 0-1; % 94.4 92.2 94.4 Median time from diagnosis (months) 30.5 24.4 30.7 Bulky disease with nodes ≥ 5 cm; % 25.7 38 31.1 Cytogenetics/FISH Category; % 17p deletion 11q deletion TP53 mutation Unmutated IGHV Complex karyotype (≥ 3 abnormalities) 9.5 17.3 11.7 57.5 16.2 8.9 17.3 10.6 66.5 17.3 9 18.6 11.9 65.5 18.1 Rai stage; % 0 I II III IV 1.7 30.2 20.1 26.8 21.2 0 26.8 24.6 27.9 20.7 0.6 28.2 27.1 22.6 21.5 The primary endpoint was progression‑free survival (PFS) of Calquence+G arm versus GClb arm as assessed by an Independent Review Committee (IRC) per International Workshop on Chronic Lymphocytic Leukaemia (IWCLL) 2008 criteria with incorporation of the clarification for treatment‑related lymphocytosis (Cheson 2012). With a median follow‑up of 28.3 months, PFS by IRC indicated a 90% statistically significant reduction in the risk of disease progression or death for previously untreated CLL patients in the Calquence+G arm compared to the GClb arm. Efficacy results are presented in Table 7. Table 7. Efficacy results per IRC Assessments in (ELEVATE‑TN) patients with CLL Calquence plus obinutuzumab N=179 Calquence monotherapy N=179 Obinutuzumab plus chlorambucil N=177 Progression‑free survival * Number of events (%) 14 (7.8) 26 (14.5) 93 (52.5) PD, n (%) 9 (5) 20 (11.2) 82 (46.3) Death events (%) 5 (2.8) 6 (3.4) 11 (6.2) Median (95% CI), months NR NR (34.2, NR) 22.6 (20.2, 27.6) HR † (95% CI) 0.10 (0.06, 0.17) 0.20 (0.13, 0.30) - P-value < 0.0001 < 0.0001 - 24 months estimate, % (95% CI) 92.7 (87.4, 95.8) 87.3 (80.9, 91.7) 46.7 (38.5, 54.6) Overall Survival a Death events (%) 9 (5) 11 (6.1) 17 (9.6) Hazard Ratio (95% CI) † 0.47 (0.21, 1.06) 0.60 (0.28, 1.27) - Best overall response rate * (CR + CRi + nPR + PR) ORR, n (%) (95% CI) 168 (93.9) (89.3, 96.5) 153 (85.5) (79.6, 89.9) 139 (78.5) (71.9, 83.9) P-value < 0.0001 0.0763 - CR, n (%) 23 (12.8) 1 (0.6) 8 (4.5) CRi, n (%) 1 (0.6) 0 0 nPR, n (%) 1 (0.6) 2 (1.1) 3 (1.7) PR, n (%) 143 (79.9) 150 (83.8) 128 (72.3) CI=confidence interval; HR=hazard ratio; NR=not reached; CR=complete response; CRi=complete response with incomplete blood count recovery; nPR=nodular partial response; PR=partial response. * Per IRC assessment. † Based on stratified Cox‑Proportional‑Hazards model. a Median OS not reached for both arms. PFS results for Calquence with or without obinutuzumab were consistent across subgroups, including high risk features. In the high risk CLL population (17p deletion, 11q deletion, TP53 mutation or unmutated IGHV), the PFS HRs of Calquence with or without obinutuzumab versus obinutuzumab plus chlorambucil was 0.08 [95% CI (0.04, 0.15)] and 0.13 [95% CI (0.08, 0.21)], respectively. Table 8. Subgroup analysis of PFS (Study ELEVATE‑TN) Calquence monotherapy Calquence + G N Hazard Ratio 95% CI N Hazard Ratio 95% CI All subjects 179 0.20 (0.13, 0.30) 179 0.10 (0.06, 0.17) Del 17P Yes No 19 160 0.20 0.20 (0.06, 0.64) (0.12, 0.31) 21 158 0.13 0.09 (0.04, 0.46) (0.05, 0.17) TP53 mutation Yes No 19 160 0.15 0.20 (0.05, 0.46) (0.12, 0.32) 21 158 0.04 0.11 (0.01, 0.22) (0.06, 0.20) Del 17P or/and TP53 mutation Yes No 23 156 0.23 0.19 (0.09, 0.61) (0.11, 0.31) 25 154 0.10 0.10 (0.03, 0.34) (0.05, 0.18) IGHV mutation Mutated Unmutated 58 119 0.69 0.11 (0.31, 1.56) (0.07, 0.19) 74 103 0.15 0.08 (0.04, 0.52) (0.04, 0.16) Del 11q Yes No 31 148 0.07 0.26 (0.02, 0.22) (0.16, 0.41) 31 148 0.09 0.10 (0.03, 0.26) (0.05, 0.20) Complex Karyotype Yes No 31 117 0.10 0.27 (0.03, 0.33) (0.16, 0.46) 29 126 0.09 0.11 (0.03, 0.29) (0.05, 0.21) With long term data, the median follow‑up was 58.2 months for Calquence+G arm, 58.1 months for Calquence arm and 58.2 months for the GClb arm. The median investigator assessed PFS for Calquence+G and Calquence monotherapy was not reached; and was 27.8 months in GClb arm. At the time of most recent data cut off, a total of 72 patients (40.7%) originally randomised to the GClb arm crossed over to Calquence monotherapy. The median overall survival had not been reached in any arm with a total of 76 deaths: 18 (10.1%) in the Calquence+G arm, 30 (16.8%) in the Calquence monotherapy arm, and 28 (15.8%) in the GClb arm. Table 9. Efficacy Results per INV assessment in (ELEVATE‑TN) Patients with CLL Calquence plus obinutuzumab N=179 Calquence monotherapy N=179 Obinutuzumab plus Chlorambucil N=177 Progression‑free survival Number of events (%) 27 (15.1) 50 (27.9) 124 (70.1) PD, n (%) 14 (7.8) 30 (16.8) 112 (63.3) Death events (%) 13 (7.3) 20 (11.2) 12 (6.8) Median (95% CI), months * NR NR (66.5, NR) 27.8 (22.6, 33.2) HR † (95% CI) 0.11 (0.07, 0.16) 0.21 (0.15, 0.30) - Overall survival Death events (%) 18 (10.1) 30 (16.8) 28 (15.8) Hazard Ratio (95% CI) † 0.55 (0.30, 0.99) 0.98 (0.58, 1.64) - CI=confidence interval; HR=hazard ratio; NR=not reached * 95% confidence interval based on Kaplan‑Meier estimation. †Estimate based on stratified Cox‑Proportional‑Hazards model for Hazard Ratio (95% CI) stratified by 17p deletion status (yes vs. no). Figure 1. Kaplan‑Meier Curve of INV‑Assessed PFS in (ELEVATE‑TN) Patients with CLL (ITT Population) Patients with Previously Untreated CLL – Fixed duration therapy Calquence in combination with venetoclax with or without obinutuzumab The safety and efficacy of CALQUENCE in combination with venetoclax with or without obinutuzumab in previously untreated CLL was evaluated in a randomised, multi-centre, open-label Phase 3 study (AMPLIFY) of 867 patients. Patients received Calquence plus venetoclax, Calquence plus venetoclax and obinutuzumab, or Investigator's choice of chemoimmunotherapy, either FCR (fludarabine plus cyclophosphamide plus rituximab) or BR (bendamustine plus rituximab). AMPLIFY included patients previously untreated for CLL without del(17p) or TP53 mutation that were 18 years of age and older. The trial allowed patients to receive antithrombotic agents except warfarin and other vitamin K antagonists. Patients were randomised in a 1:1:1 ratio into 3 arms to receive: • Calquence plus venetoclax (AV): Calquence 100 mg was administered twice daily starting on Cycle 1 Day 1 for a total of 14 cycles or until disease progression or unacceptable toxicity. On Cycle 3 Day 1 patients started the venetoclax 5‑week dose‑titration schedule, starting at 20 mg and increasing weekly to 50 mg, 100 mg, 200 mg and finally 400 mg once daily. Venetoclax was administered for a total of 12 cycles. Each cycle was 28 days. • Calquence plus venetoclax plus obinutuzumab (AVO): Calquence 100 mg was administered twice daily starting on Cycle 1 Day 1 for a total of 14 cycles or until disease progression or unacceptable toxicity. On Cycle 3 Day 1 patients started the venetoclax 5‑week dose‑titration schedule, starting at 20 mg and increasing weekly to 50 mg, 100 mg, 200 mg and finally 400 mg once daily. Venetoclax was administered for a total of 12 cycles. Obinutuzumab 1 000 mg was administered on Day 1 or Day 1 and 2 (100 mg on Day 1 and 900 mg on Day 1 or 2), 8 and 15 of Cycle 2 followed by 1 000 mg on Day 1 of Cycles 3‑7. Each cycle was 28 days. • Investigator's choice of chemoimmunotherapy (FCR/BR): o Fludarabine plus cyclophosphamyde plus rituximab (FCR): Fludarabine (25 mg/m 2 ) and cyclophosphamide (250 mg/m 2 ) were administered on Days 1‑3 up to a maximum of 6 cycles. Rituximab was administered at a dose of 375 mg/m 2 on Day 1 Cycle 1 and 500 mg/m 2 on Day 1 of Cycles 2 up to 6. Each cycle was 28 days. o Bendamustine plus rituximab (BR): Bendamustine 90 mg/m 2 was administered on Days 1 and 2 up to maximum of 6 cycles. Rituximab was administered at a dose of 375 mg/m 2 on Day 1 Cycle 1 and 500 mg/m 2 on Day 1 of Cycles 2 up to 6. Each cycle was 28 days. Patients were stratified by age (>65 years or ≤65 years), IGHV mutational status (mutated versus unmutated), Rai stage (high risk [≥3] versus non-high risk) and geographic region (North America and Western Europe versus other). Table 10 summarises the baseline demographics and disease characteristics of the study population. Table 10. Baseline Patient Characteristics in (AMPLIFY) Patients with Previously Untreated CLL Characteristic AV N=291 AVO N=286 FCR/BR N=290 Age, years; median (range) 61 (31‑84) 61 (29‑81) 61 (26‑86) Male; % 61.2 69.2 63.1 Caucasian; % 91.1 86.7 86.9 ECOG performance status 0-1; % 90.0 95.1 90.3 Median time from diagnosis to randomization (months) 28.5 26.1 29.6 Bulky disease with nodes ≥ 5 cm; % 38.8 35.0 42.8 Cytogenetics/FISH Category; % 11q deletion 17.5 19.6 15.9 Complex karyotype (≥ 3 abnormalities) 15.5 16.1 14.5 Unmutated IGHV; % 57.4 59.1 59.3 Rai stage; % 0 1.0 0.3 1.4 I 16.2 21.3 21.4 II 35.7 37.8 33.4 III 23.7 17.8 20.3 IV 23.4 22.7 23.4 The primary endpoint was IRC‑assessed PFS for AV versus Investigator's choice of chemoimmunotherapy (FCR/BR) arm as assessed by IWCLL 2018 criteria. Additional efficacy endpoints were IRC-assessed PFS of AVO versus Investigator's choice (FCR/BR) arm and OS in both AV arm vs. Investigator's choice (FCR/BR) arm and AVO vs. Investigator's choice (FCR/BR) arm. Efficacy results are presented in Table 11. The Kaplan-Meier curve for IRC-PFS is shown in Figure 2. Table 11. Efficacy results in (AMPLIFY) patients with previously untreated CLL AV N=291 AVO N=286 FCR/BR a N=290 Progression-free survival * Number of events (%) 89 (30.6) 56 (19.6) 95 (32.8) PD, n (%) 77 (26.5) 23 (8.0) 66 (22.8) Death events (%) 12 (4.1) 33 (11.5) 29 (10.0) Median (95% CI), months NC (51.1, NC) NC (NC, NC) 47.6 (43.3, NC) HR † (95% CI) 0.65 (0.49, 0.87) 0.42 (0.30, 0.59) - P-value 0.0038 ˂0.0001 - Overall Survival b Death events (%) 23 (7.9) 37 (12.9) 44 (15.2) HR † (95% CI) 0.42 (0.25, 0.70) c 0.75 (0.48, 1.16) - NC= Not calculable. * Per IRC assessment. † Based on stratified Cox-Proportional-Hazards model. a Per Investigator's choice 143 patients were planned to receive FCR and 147 patients were planned to receive BR. b OS data at additional 6 months follow-up from PFS interim analysis. c The p-value is not significant after adjusting for multiplicity. Figure 2. Kaplan-Meier Curve of IRC-Assessed PFS in (AMPLIFY) patients with CLL (ITT Population) Patients with CLL who received at least one prior therapy The safety and efficacy of Calquence in relapsed or refractory CLL were evaluated in a randomised, multi‑centre, open‑label phase 3 study (ASCEND) of 310 patients who received at least one prior therapy not including BCL‑2 inhibitors or B‑cell receptor inhibitors. Patients received Calquence monotherapy or investigator's choice of either idelalisib plus rituximab or bendamustine plus rituximab. The study allowed patients to receive antithrombotic agents. Patients who required anticoagulation with warfarin or equivalent vitamin K antagonists were excluded. Patients were randomised 1:1 to receive either: • Calquence 100 mg twice daily until disease progression or unacceptable toxicity, or • Investigator's choice: o Idelalisib 150 mg twice daily in combination with rituximab 375 mg/m2 IV on Day 1 of the first cycle, followed by 500 mg/m2 IV every 2 weeks for 4 doses, then every 4 weeks for 3 doses for a total of 8 infusions o Bendamustine 70 mg/m 2 (Day 1 and 2 of each 28‑day cycle) in combination with rituximab (375 mg/m 2 /500 mg/m 2 ) on Day 1 of each 28‑day cycle for up to 6 cycles Patients were stratified by 17p deletion mutation status (presence versus absence), ECOG performance status (0 or 1 versus 2) and number of prior therapies (1 to 3 versus ≥ 4). After confirmed disease progression, 35 patients randomised on investigator's choice of either idelalisib plus rituximab or bendamustine plus rituximab crossed over to Calquence. Table 12 summarizes the baseline demographics and disease characteristics of the study population. Table 12. Baseline patient characteristics in (ASCEND) patients with CLL Characteristic Calquence monotherapy N=155 Investigator's choice of idelalisib + rituximab or bendamustine + rituximab N=155 Age, years; median (range) 68 (32-89) 67 (34-90) Male; % 69.7 64.5 Caucasian; % 93.5 91.0 ECOG performance status; % 0 37.4 35.5 1 50.3 51.0 2 12.3 13.5 Median time from diagnosis (months) 85.3 79.0 Bulky disease with nodes ≥ 5 cm; % 49.0 48.4 Median number of prior CLL therapies (range) 1 (1-8) 2 (1-10) Number of Prior CLL Therapies; % 1 52.9 43.2 2 25.8 29.7 3 11.0 15.5 ≥ 4 10.3 11.6 Cytogenetics/FISH Category; % 17p deletion 18.1 13.5 11q deletion 25.2 28.4 TP53 mutation 25.2 21.9 Unmutated IGHV 76.1 80.6 Complex karyotype (≥3 abnormalities) 32.3 29.7 Rai Stage; % 0 1.3 2.6 I 25.2 20.6 II 31.6 34.8 III 13.5 11.6 IV 28.4 29.7 The primary endpoint was PFS as assessed by IRC IWCLL 2008 criteria with incorporation of the clarification for treatment‑related lymphocytosis (Cheson 2012). With a median follow‑up of 16.1 months, PFS indicated a 69% statistically significant reduction in the risk of death or progression for patients in the Calquence arm. Efficacy results are presented in Table 13. The Kaplan‑Meier curve for PFS is shown in Figure 3. Table 13. Efficacy results per IRC Assessments in (ASCEND) patients with CLL Calquence monotherapy N=155 Investigator's choice of idelalisib + rituximab or bendamustine + rituximab N=155 Progression‑free survival * Number of events (%) 27 (17.4) 68 (43.9) PD, n (%) 19 (12.3) 59 (38.1) Death events (%) 8 (5.2) 9 (5.8) Median (95% CI), months NR 16.5 (14.0, 17.1) HR † (95% CI) 0.31 (0.20, 0.49) P-value < 0.0001 15 months estimate, % (95% CI) 82.6 (75.0, 88.1) 54.9 (45.4, 63.5) Overall survival a Death events (%) 15 (9.7) 18(11.6) Hazard Ratio (95% CI) † 0.84 (0.42, 1.66) - Best overall response rate * (CR + CRi + nPR + PR)** ORR, n (%) (95% CI) 126 (81.3) (74.4, 86.6) 117 (75.5) (68.1, 81.6) P-value 0.2248 - CR, n (%) 0 2 (1.3) PR, n (%) 126 (81.3) 115 (74.2) Duration of Response (DoR) Median (95% CI), months NR 13.6 (11.9,NR) CI=confidence interval; HR=hazard ratio; NR=not reached; CR=complete response; CRi=complete response with incomplete blood count recovery; nPR=nodular partial response; PR=partial response; PD=progressive disease. * Per IRC assessment. a Median OS not reached for both arms. P<0.6089 for OS. **CRi and nPR have values of 0. † Based on stratified Cox‑Proportional‑Hazards model. Figure 3. Kaplan‑Meier curve of IRC‑assessed PFS in (ASCEND) patients with CLL (ITT Population) PFS results for Calquence were consistent across subgroups, including high risk features. In the high risk CLL population (17p deletion, 11q deletion, TP53 mutation and unmutated IGHV), the PFS HR was 0.27 [95% CI (0.17, 0.44)]. Table 14. Subgroup analysis of IRC‑assessed PFS (Study ASCEND) Calquence monotherapy N Hazard Ratio 95% CI All subjects 155 0.30 (0.19, 0.48) Del 17P Yes No 28 127 0.21 0.33 (0.07, 0.68) (0.21, 0.54) TP53 mutation Yes No 39 113 0.24 0.33 (0.11, 0.56) (0.20, 0.57) Del 17P or TP53 mutation Yes No 45 108 0.21 0.36 (0.09, 0.48) (0.21, 0.61) IGHV mutation Mutated Unmutated 33 118 0.32 0.32 (0.11, 0.94) (0.19, 0.52) Del 11q Yes No 39 116 0.28 0.31 (0.11, 0.70) (0.19, 0.53) Complex Karyotype Yes No 50 97 0.32 0.23 (0.16, 0.63) (0.12, 0.44) At final analysis, with a median follow‑up of 46.5 months for Calquence and 45.3 months for the IR/BR, a 72% reduction in risk of investigator‑assessed disease progression or death was observed for patients in the Calquence arm. The median investigator assessed PFS was not reached in Calquence and was 16.8 months in IR/BR. Efficacy results per Investigator Assessments (INV) are presented in Table 15. The Kaplan‑Meier curve for INV assessed PFS is shown in Figure 4. Table 15. Efficacy results at final analysis per INV assessments in (ASCEND) patients with CLL Calquence monotherapy N=155 Investigator's choice of idelalisib + rituximab or bendamustine + rituximab N=155 Progression‑free survival * Number of events (%) 62 (40.0) 119 (76.8) PD, n (%) 43 (27.7) 102 (65.8) Death events (%) 19 (12.3) 17 (11.0) Median (95% CI), months NR 16.8 (14.1, 22.5) HR † (95% CI) 0.28 (0.20, 0.38) Overall survival a Death events (%) 41 (26.5) 54 (34.8) Hazard Ratio (95% CI) † 0.69 (0.46, 1.04) - CI=confidence interval; HR=hazard ratio; NR=not reached; PD=progressive disease. * Per INV assessment. a Median OS not reached for both arms P=0.0783 for OS. † Based on stratified Cox‑Proportional‑Hazards model. Figure 4. Kaplan‑Meier curve of INV‑assessed PFS at final analysis in (ASCEND) patients with CLL Investigator assessed PFS results at final analysis for Calquence were consistent across subgroups, including high risk features and were consistent with the primary analysis. Patients with previously untreated MCL The safety and efficacy of Calquence in patients with previously untreated MCL was evaluated in ECHO, a randomised, double-blind, placebo-controlled, multi-centre, phase 3 study. ECHO included 598 patients 65 years of age and older with confirmed MCL that was previously untreated. Patients were randomised in 1:1 ratio in 2 arms to receive: • Calquence plus bendamustine and rituximab (Calquence + BR) arm - Calquence 100 mg was administered twice daily from Day 1 of Cycle 1, continuously. Bendamustine, 90 mg/m 2 , was intravenously administered over 30 minutes on Days 1 and 2 of each of six 28‑day cycles; and rituximab, 375 mg/m 2 , was intravenously administered on Day 1 of each cycle of six 28‑day cycles. Calquence + BR was administered for a maximum of 6 treatment cycles (induction treatment). • Placebo plus bendamustine and rituximab (Placebo + BR) arm – Placebo was administered twice daily from Day 1 of Cycle 1, continuously. Bendamustine, 90 mg/m 2 , was intravenously administered over 30 minutes on Days 1 and 2 of each of six 28‑day cycles; and rituximab, 375 mg/m 2 , was intravenously administered on Day 1 of each cycle of six 28‑day cycles. Placebo + BR was administered for a maximum of 6 treatment cycles (induction treatment). Calquence or placebo was administered continuously until disease progression or unacceptable toxicity. After the induction treatment, patients who were achieving a response (PR or CR) received rituximab maintenance at 375 mg/m 2 on Day 1 of every other cycle for maximum of 12 additional doses up to Cycle 30. Patients randomised to placebo + BR arm, who had confirmed PD were eligible to cross over to Calquence monotherapy at 100 mg twice daily dose until their second disease progression or unacceptable toxicity. Patient randomisation was stratified by geographic region (North America versus Western Europe versus Other) and simplified MIPI (Mantle Cell Lymphoma International Prognostic Index) score (0‑3 versus 4‑5 versus 6‑11). The median age was 71 years (65‑86), 70.7% were males, 78.3% were Caucasians, 93.1% had an ECOG performance status of 0‑1. The simplified MIPI score was low (0-3) in 33.1%, intermediate (4-5) in 42.8% and high (6-11) in 24.1% of patients. A total of 37.7% of patients had tumour bulk ≥ 5 cm and 86% had Ann Arbor stage IV disease. Aggressive variants of MCL such as blastoid and pleomorphic forms were seen in 7.7% and 5.5% of patients respectively. A total of 47.8% patients had Ki-67 score of ≥ 30%. The baseline characteristics were similar for both arms. The primary endpoint was progression-free survival (PFS) as assessed by an Independent Review Committee (IRC) per 2014 Lugano Classification for non-Hodgkin's lymphoma (NHL) in subjects with previously untreated MCL. Additional efficacy endpoints were Investigator-assessed (INV) PFS, INV and IRC assessed overall response rate (ORR), IRC and INV assessed duration of response (DOR) and overall survival (OS). With a median follow-up of 46.1 months, IRC‑assessed PFS demonstrated 27% statistically significant reduction in risk of disease progression or death in patients treated with Calquence + BR compared to BR. With an additional 6 months of follow-up from the primary PFS analysis, and a median follow-up of 63.0 months, the median overall survival had not been reached in either arm. There were a total of 218 deaths: 105 (35.1%) in the Calquence + BR arm and 113 (37.8%) in the placebo + BR arm. Efficacy results are presented in Table 16. The Kaplan-Meier curves for PFS are shown in Figure 5. Table 16. Efficacy Results in Patients with previously untreated MCL in ECHO Calquence + BR N=299 Placebo + BR N=299 IRC‑assessed PFS Median (95% CI), months 66.4 (55.1, NE) 49.6 (36.0, 64.1) HR (95% CI) (stratified) * 0.73 (0.57, 0.94) p-value ‡ 0.0160 IRC‑assessed ORR CR + PR n (%) 272 (91.0) 263 (88.0) 95% CI 87.3,93.8 83.9, 91.3 CR n (%) 199 (66.6) 160 (53.5) PR n (%) 73 (24.4) 103 (34.4) ORR difference (vs PBR arm) 3.0% - p-value 0.2196 - IRC‑assessed DOR Median (95% CI), months 63.5 (52.5, NE) 53.8 (37.6, 66.1) * Stratified by randomisation stratification factors: Geographic Regions (North American, Western Europe, Other) and simplified MIPI Score (Low risk [0 to 3], Intermediate risk [4 to 5], High Risk [6 to 11]) as collected via IXRS. Estimated based on stratified Cox Proportional Hazards model for hazard ratio (95% CI). ‡ Estimated based on stratified log-rank test for p-value. Figure 5. Kaplan-Meier Curve of IRC-Assessed PFS in patients with previously untreated MCL (ECHO) Patients with MCL who received at least one prior therapy The safety and efficacy of Calquence in MCL were evaluated in an open-label, multi-centre, single‑arm Phase 2 study (ACE-LY-004) of 124 previously treated patients. All patients received Calquence 100 mg orally twice daily until disease progression or unacceptable toxicity. The trial did not include patients who received prior treatment with either BTK or BCL-2 inhibitors. The primary endpoint was investigator‑assessed overall response rate (ORR) per the Lugano classification for non-Hodgkin's lymphoma (NHL). Duration of Response (DoR) was an additional outcome measure. Efficacy results at final (54 months) analysis are presented in Table 17. At final analysis, the median age was 68 (range 42 to 90) years, 79.8% were male and 74.2% were Caucasian. At baseline, 92.8% of patients had an ECOG performance status of 0 or 1. The median time since diagnosis was 46.3 months and the median number of prior treatments was 2 (range 1 to 5), including 17.7% with prior stem cell transplant. The most common prior regimens were CHOP-based (51.6%) and ARA-C (33.9%). At baseline, 37.1% of patients had at least one tumour with a longest diameter ≥ 5 cm, 72.6% had extra nodal involvement including 50.8% with bone marrow involvement. The simplified MIPI score (which includes age, ECOG score, and baseline lactate dehydrogenase and white cell count) was intermediate in 43.5% and high in 16.9% of patients. Table 17. ORR and DOR in (ACE-LY-004) Patients with MCL at 54 months final analysis Investigator Assessment at 54 months N=124 n (%) (95% CI * ) Overall Response Rate (ORR) Overall Response Rate 101 (81.5%) (73.5, 87.9) Complete Response 59 (47.6%) (38.5, 56.7) Partial Response 42 (33.9%) (25.6, 42.9) Non-Evaluable † 3 (2.4%) (0.5, 6.9) Duration of Response (DoR) Median (months) 28.6 (17.5, 39.1) CI=Confidence Interval * 95% exact binomial confidence interval. † Includes subjects without any adequate post-baseline disease assessment. Paediatric population The Licencing Authority has waived the obligation to submit the results of studies with Calquence in all subsets of the paediatric population for the treatment of mature B-cell neoplasms (for information on paediatric use, see section 4.2).