Protein Kinase Inhibitor.
Pharmacology: Mechanism of action: Ibrutinib is a potent, small‑molecule inhibitor of Bruton's tyrosine kinase (BTK). Ibrutinib forms a covalent bond with a cysteine residue (Cys‑481) in the BTK active site, leading to sustained inhibition of BTK enzymatic activity. BTK, a member of the Tec kinase family, is an important signaling molecule of the B‑cell antigen receptor (BCR) and cytokine receptor pathways. The BCR pathway is implicated in the pathogenesis of several B‑cell malignancies, including MCL, diffuse large B‑cell lymphoma (DLBCL), follicular lymphoma, and B-cell CLL. BTK's pivotal role in signaling through the B‑cell surface receptors results in activation of pathways necessary for B‑cell trafficking, chemotaxis and adhesion. Preclinical studies have shown that ibrutinib inhibits malignant B‑cell proliferation and survival
in vivo as well as cell migration and substrate adhesion
in vitro.
BTK inhibition by ibrutinib increases CLL cell dependence on BCL-2, a cell survival pathway, while venetoclax inhibits BCL-2 leading to apoptosis. In preclinical tumor models, the combination of ibrutinib and venetoclax resulted in increased cellular apoptosis and anti-tumor activity compared to either agent alone.
Lymphocytosis: Upon initiation of single agent treatment with Ibrutinib (Imbruvica), a reversible increase in lymphocyte counts (i.e., ≥50% increase from baseline and an absolute count >5,000/mcL), often associated with reduction of lymphadenopathy, has been observed in most patients (66%) with CLL/SLL. This effect has also been observed in some patients (35%) with MCL treated with Ibrutinib (Imbruvica). This observed lymphocytosis is a pharmacodynamic effect and should not be considered progressive disease in the absence of other clinical findings. In both disease types, lymphocytosis typically occurs during the first month of Ibrutinib (Imbruvica) therapy and typically resolves within a median of 8 weeks in patients with MCL and 14 weeks in patients with CLL/SLL (range, 0.1 to 104 weeks).
When Ibrutinib (Imbruvica) was administered in combination with BR or with obinutuzumab in subjects with CLL/SLL, lymphocytosis was infrequent (7% with Ibrutinib (Imbruvica) + BR versus 6% with placebo + BR and 7% with Ibrutinib (Imbruvica) + obinutuzumab versus 1% with chlorambucil + obinutuzumab).
Lymphocytosis was not observed in patients with WM treated with Ibrutinib (Imbruvica).
In vitro platelet aggregation: In an
in vitro study, ibrutinib demonstrated inhibition of collagen-induced platelet aggregation in samples from the cohorts of subjects with either renal dysfunction, those on warfarin, or healthy subjects. The magnitude of inhibition of collagen-induced platelet aggregation in the cohort of subjects on aspirin was less pronounced since collagen-induced platelet aggregation was already reduced without ibrutinib. Ibrutinib did not show meaningful inhibition of platelet aggregation for the 4 agonists adenosine diphosphate (ADP), arachidonic acid, ristocetin, and thrombin receptor-activating peptide 6 (TRAP-6) across any of these cohorts of subjects or healthy subjects.
Effect on QT/QTc interval and cardiac electrophysiology: The effect of ibrutinib on the QTc interval was evaluated in 20 healthy male and female subjects in a randomized, double-blind thorough QT study with placebo and positive controls. At a supratherapeutic dose of 1680 mg, ibrutinib did not prolong the QTc interval to any clinically relevant extent. The largest upper bound of the 2-sided 90% CI for the baseline adjusted mean differences between ibrutinib and placebo was below 10 ms. In this same study, a concentration dependent shortening in the QTc interval was observed (-5.3 ms [90% CI: -9.4, -1.1] at a C
max of 719 ng/mL following the supratherapeutic dose of 1680 mg) that was considered not clinically relevant.
Clinical studies: Mantle cell lymphoma: The safety and efficacy of Ibrutinib (Imbruvica) in MCL patients who received at least one prior therapy were evaluated in a single open-label, multi-center phase 2 study (PCYC-1104-CA) of 111 patients. The median age was 68 years (range, 40 to 84 years), 77% were male and 92% were Caucasian. The median time since diagnosis was 42 months, and median number of prior treatments was 3 (range, 1 to 5 treatments), including 35% with prior high-dose chemotherapy, 43% with prior bortezomib, 24% with prior lenalidomide, and 11% with prior autologous or allogeneic stem cell transplant. At baseline, 39% of patients had bulky disease (≥5 cm), 49% had high-risk score by Simplified MCL International Prognostic Index (MIPI), and 72% had advanced disease (extranodal and/or bone marrow involvement) at screening.
Ibrutinib (Imbruvica) was administered orally at 560 mg once daily until disease progression or unacceptable toxicity. Tumor response was assessed according to the revised International Working Group (IWG) for non-Hodgkin's lymphoma (NHL) criteria. The primary endpoint in this study was investigator-assessed overall response rate (ORR). Responses to Ibrutinib (Imbruvica) are shown in Table 1. (See Table 1.)
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The efficacy data was further evaluated by an Independent Review Committee (IRC) demonstrating an ORR of 69%, with a 21% CR rate and a 48% PR rate. The IRC estimated median DOR was 19.6 months.
The overall response to Ibrutinib (Imbruvica) was independent of prior treatment including bortezomib and lenalidomide or underlying risk/prognosis, bulky disease, gender or age (Figure 1). (See Figure 1.)
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The safety and efficacy of Ibrutinib (Imbruvica) were demonstrated in a randomized phase 3, open-label, multicenter study including 280 patients with MCL who received at least one prior therapy (Study MCL3001). Patients were randomized 1:1 to receive either Ibrutinib (Imbruvica) orally at 560 mg once daily on a 21-day cycle or temsirolimus intravenously at 175 mg on Days 1, 8, 15 of the first cycle followed by 75 mg on Days 1, 8, 15 of each subsequent 21-day cycle. Treatment on both arms continued until disease progression or unacceptable toxicity. The median age was 68 years (range, 34 to 88 years), 74% were male and 87% were Caucasian. The median time since diagnosis was 43 months, and median number of prior treatments was 2 (range: 1 to 9 treatments), including 51% with prior high-dose chemotherapy, 18% with prior bortezomib, 5% with prior lenalidomide, and 24% with prior stem cell transplant. At baseline, 53% of patients had bulky disease (≥5 cm), 21% had high-risk score by Simplified MIPI, 60% had extranodal disease and 54% had bone marrow involvement at screening.
Progression-free survival (PFS) was assessed by IRC according to the revised IWG for non-Hodgkin's lymphoma (NHL) criteria showed a 57% statistically significant reduction in the risk of death or progression for patients in the Ibrutinib (Imbruvica) arm. Efficacy results for Study MCL3001 are shown in Table 2 and the Kaplan-Meier curve for PFS in Figure 2. (See Table 2.)
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A smaller proportion of patients treated with Ibrutinib (Imbruvica) experienced a clinically meaningful worsening of lymphoma symptoms versus temsirolimus (27% versus 52%) and time to worsening of symptoms occurred more slowly with Ibrutinib (Imbruvica) versus temsirolimus (HR 0.27, p <0.0001). (See Figure 2.)
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Chronic lymphocytic leukemia/Small lymphocytic lymphoma: The safety and efficacy of Ibrutinib (Imbruvica) in patients with CLL/SLL were demonstrated in two uncontrolled study and six randomized, controlled studies.
Patients with treatment-naïve CLL/SLL: Single agent: Study PCYC-1115-CA: A randomized, multicenter, open-label phase 3 study of Ibrutinib (Imbruvica) versus chlorambucil was conducted in patients with treatment-naïve CLL/SLL who were 65 years of age or older. Patients (n=269) were randomized 1:1 to receive either Ibrutinib (Imbruvica) 420 mg daily until disease progression or unacceptable toxicity, or chlorambucil at a starting dose of 0.5 mg/kg on Days 1 and 15 of each 28-day cycle for a maximum of 12 cycles, with an allowance for intrapatient dose increases up to 0.8 mg/kg based on tolerability. After confirmed disease progression, patients on chlorambucil were able to crossover to ibrutinib.
The median age was 73 years (range, 65 to 90 years), 63% were male, and 91% were Caucasian. Ninety-one percent of patients had a baseline Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and 9% had an ECOG performance status of 2. The study enrolled 269 patients with CLL or SLL. At baseline, 45% had advanced clinical stage (Rai Stage III or IV), 35% of patients had at least one tumor ≥5 cm, 39% with baseline anemia, 23% with baseline thrombocytopenia, 65% had elevated β2 microglobulin >3500 mcg/L, 47% had a CrCL <60 mL/min, and 20% of patients presented with del 11q, 6% of patients presented with del 17p/tumor protein 53 (TP53) mutation, and 44% of patients presented with unmutated immunoglobulin heavy chain variable region (IGHV).
Progression-free survival (PFS) as assessed by IRC according to International Workshop on CLL (IWCLL) criteria indicated an 84% statistically significant reduction in the risk of death or progression in the Ibrutinib (Imbruvica) arm. With a median follow-up of 18 months, the median PFS was not reached in the ibrutinib arm and was 19 months in the chlorambucil arm. Significant improvement in the ORR was observed in the ibrutinib arm (82%) versus the chlorambucil arm (35%). The results from the investigator and IRC assessments for PFS and ORR were consistent. Analysis of overall survival (OS) also demonstrated an 84% statistically significant reduction in the risk of death for patients in the Ibrutinib (Imbruvica). Efficacy results for Study PCYC-1115-CA are shown in Table 3 and the Kaplan-Meier curves for PFS and OS are shown in Figures 3 and 4, respectively.
There was a statistically significant sustained platelet or hemoglobin improvement in the ITT population in favor of ibrutinib versus chlorambucil. In patients with baseline cytopenias, sustained hematologic improvement was: platelets 77% versus 43%; hemoglobin 84% versus 45% for ibrutinib and chlorambucil respectively. (See Table 3, Figures 3 and 4.)
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Overall follow-up of 55 months (medial of 48 months): With an overall follow-up of 55 months (median of 48 months) in Study PCYC-1115-CA and its extension study, an 86% reduction in the risk of death or progression by investigator assessment was observed for patients in the Ibrutinib (Imbruvica) arm. The median investigator-assessed PFS was not reached in the Ibrutinib (Imbruvica) arm and was 15 months [95% CI (10.22, 19.35)] in the chlorambucil arm; (HR = 0.14 [95% CI (0.09, 0.21)]). The 4-year PFS estimate was 73.9% in the Ibrutinib (Imbruvica) arm and 15.5% in the chlorambucil arm, respectively. The updated Kaplan-Meier curve for PFS is shown in Figure 5. The investigator-assessed ORR was 91.2% in the Ibrutinib (Imbruvica) arm versus 36.8% in the chlorambucil arm. The CR rate according to IWCLL criteria was 16.2% in the Ibrutinib (Imbruvica) arm versus 3.0% in the chlorambucil arm. At the time of long-term follow-up, a total of 73 subjects (54.9%) originally randomized to the chlorambucil arm subsequently received ibrutinib as cross-over treatment. The Kaplan-Meier landmark estimate for OS at 48-months was 85.5% in the Ibrutinib (Imbruvica) arm.
The treatment effect of ibrutinib in Study PCYC-1115-CA was consistent across high-risk patients with del 17p/TP53 mutation, del 11q, and/or unmutated IGHV. (See Figure 5.)
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Combination therapy: Study PCYC-1130-CA: A randomized, multi-center, open-label, phase 3 study of Ibrutinib (Imbruvica) in combination with obinutuzumab versus chlorambucil in combination with obinutuzumab was conducted in patients with treatment naïve CLL/SLL. The study enrolled patients who were 65 years of age or older or <65 years of age with coexisting medical conditions, reduced renal function as measured by creatinine clearance <70 mL/min, or presence of del 17p/TP53 mutation. Patients (n=229) were randomized 1:1 to receive either Ibrutinib (Imbruvica) 420 mg daily until disease progression or unacceptable toxicity or chlorambucil at a dose of 0.5 mg/kg on Days 1 and 15 of each 28-day cycle for 6 cycles. In both arms, patients received 1000 mg of obinutuzumab on Days 1, 8 and 15 of the first cycle, followed by treatment on the first day of 5 subsequent cycles (total of 6 cycles, 28 days each). The first dose of obinutuzumab was divided between day 1 (100 mg) and day 2 (900 mg).
The median age was 71 years (range, 40 to 87 years), 64% were male, and 96% were Caucasian. All patients had a baseline ECOG performance status of 0 (48%) or 1-2 (52%). At baseline, 52% had advanced clinical stage (Rai Stage III or IV), 32% of patients had bulky disease (≥5 cm), 44% with baseline anemia, 22% with baseline thrombocytopenia, 28% had a CrCL <60 mL/min, and the median Cumulative Illness Rating Score for Geriatrics (CIRS-G) was 4 (range, 0 to 12). At baseline, 65% of patients presented with CLL/SLL with high risk factors (del 17p/TP53 mutation [18%], del 11q [15%], or unmutated IGHV [54%]).
Progression-free survival (PFS) as assessed by IRC according to IWCLL criteria indicated a 77% statistically significant reduction in the risk of death or progression in the Ibrutinib (Imbruvica) arm. With a median follow-up time on study of 31 months, the median PFS was not reached in the Ibrutinib (Imbruvica) + obinutuzumab arm and was 19 months in the chlorambucil + obinutuzumab arm. The results from investigator and IRC assessments for PFS and ORR were consistent.
Efficacy results for Study PCYC-1130-CA are shown in Table 4 and the Kaplan-Meier curve for PFS is shown in Figure 6. (See Table 4 and Figure 6.)
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The treatment effect of ibrutinib was consistent across the high-risk CLL/SLL population (del 17p/TP53 mutation, del 11q, or unmutated IGHV), with a PFS HR of 0.15 [95% CI (0.09, 0.27)], as shown in Table 5. The 2-year PFS rate estimates for the high-risk CLL/SLL population were 78.8% [95% CI (67.3, 86.7)] and 15.5% [95% CI (8.1, 25.2)] in the Ibrutinib (Imbruvica) + obinutuzumab and chlorambucil + obinutuzumab arms, respectively. (See Table 5.)
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Any grade infusion-related reactions were observed in 25% of patients treated with Ibrutinib (Imbruvica) + obinutuzumab and 58% of patients treated with chlorambucil + obinutuzumab. Grade 3 or higher or serious infusion-related reactions were observed in 3% of patients treated with Ibrutinib (Imbruvica) + obinutuzumab and 9% of patients treated with chlorambucil + obinutuzumab.
Study E1912: A randomized, multi-center, open-label, safety and efficacy, Phase 3 study of Ibrutinib (Imbruvica) in combination with rituximab versus standard fludarabine, cyclophosphamide, and rituximab [FCR] chemoimmunotherapy was conducted in patients with treatment naïve CLL/SLL who were 70 years or younger. Patients (n=529) were randomized 2:1 to receive either IR or FCR. Ibrutinib (Imbruvica) was administered at 420 mg daily until disease progression or unacceptable toxicity. Fludarabine was administered at a dose of 25 mg/m
2, and cyclophosphamide was administered at a dose of 250 mg/m
2, both on Days 1, 2, and 3 of Cycles 1-6. Rituximab was initiated in Cycle 2 for the IR arm and in Cycle 1 for the FCR arm and was administered at 50 mg/m
2 on Day 1 of the first cycle, 325 mg/m
2 on Day 2 of the first cycle, and 500 mg/m
2 on Day 1 of 5 subsequent cycles, for a total of 6 cycles. Each cycle was 28 days.
The median age was 58 years (range, 28 to 70 years), 67% were male, and 90% were Caucasian. All patients had a baseline ECOG performance status of 0-1 (98%) or 2 (2%). At baseline, 43% of patients presented with Rai stage III or IV, and 59% of patients presented with CLL/SLL with high risk factors (TP53 mutation [6%], del11q [22%], or unmutated IGHV [53%]).
With a median follow-up time on study of 37 months, efficacy results for E1912 are shown in Table 6. The Kaplan-Meier curves for PFS, assessed according to IWCLL criteria, and OS are shown in Figures 7 and 8, respectively. (See Table 6 and Figure 7.)
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The treatment effect of ibrutinib was consistent across the high-risk CLL/SLL population (del17p/TP53 mutation, del11q, or unmutated IGHV), with a PFS HR of 0.23 [95% CI (0.13, 0.40)], p <0.0001, as shown in Table 7. The 3-year PFS rate estimates for the high-risk CLL/SLL population were 90.4% [95% CI (85.4, 93.7)] and 60.3% [95% CI (46.2, 71.8)] in the IR and FCR arms, respectively. (See Table 7 and Figure 8.)
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Fixed duration combination therapy: Study PCYC-1142-CA: A Phase 2, multi-center, 2-cohort study assessing both minimal residual disease (MRD)-guided discontinuation and fixed duration therapy with Ibrutinib (Imbruvica) in combination with venetoclax, was conducted in adult patients who were 70 years or younger with previously untreated CLL or SLL. The study enrolled 323 patients, of these, 159 patients were enrolled to fixed duration therapy consisting of 3 cycles of single agent Ibrutinib (Imbruvica) followed by Ibrutinib (Imbruvica) in combination with venetoclax for 12 cycles (including 5-week dose ramp-up). Each cycle was 28 days. Ibrutinib (Imbruvica) was administered at a dose of 420 mg daily. Venetoclax was administered daily, starting with 20 mg for 1 week, followed by 1 week at each dose level of 50 mg, 100 mg, and 200 mg, then the recommended daily dose of 400 mg. Patients with confirmed progression by IWCLL criteria after completion of the fixed duration regimen could be retreated with single-agent Ibrutinib (Imbruvica).
The median age was 60 years (range, 33 to 71 years), 67% were male, and 92% were White. All patients had a baseline ECOG performance status of 0 (69%) or 1 (31%). The trial enrolled 146 patients with CLL and 13 patients with SLL. At baseline, 13% of patients had CLL/SLL with del 17p, 18% with del 11q, 17% with del 17p/TP53 mutation, 56% with unmutated IGHV and 19% with complex karyotype. The most common reasons for initiating CLL therapy included: lymphadenopathy (65%), progressive lymphocytosis (51%), splenomegaly (30%), fatigue (24%), progressive marrow failure demonstrated by anemia and/or thrombocytopenia (23%), and night sweats (21%). At baseline assessment for risk of tumor lysis syndrome, 21% of patients had high tumor burden. After 3 cycles of single-agent Ibrutinib (Imbruvica) lead-in therapy, 1% of patients had high tumor burden. High tumor burden was defined as any lymph node ≥10 cm, or any lymph node ≥5 cm and absolute lymphocyte count ≥25x10
9/L.
With a median follow-up time on study of 28 months, efficacy results for PCYC-1142-CA assessed by an IRC according to IWCLL criteria are shown in Table 8, and rates of minimal residual disease (MRD) negativity are shown in Table 9. (See Tables 8 and 9.)
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At this assessment, 84 patients who were MRD negative in peripheral blood had matched bone marrow specimens; of these, 76 patients (90%) were MRD negative in both peripheral blood and bone marrow.
In the fixed duration cohort, no TLS was reported in patients treated with Ibrutinib (Imbruvica) in combination with venetoclax.
CLL/SLL with del 17p/TP53 in PCYC-1142-CA: In patients with del 17p/TP53 mutation (n=27) the overall response rate based on IRC assessment was 96.3%; complete response rate was 55.6% and the median duration of complete response was not reached (range, 4.3 to 22.6 months). The MRD negativity rate in patients with del 17p/TP53 mutation 3 months after completion of treatment in bone marrow and peripheral blood was 40.7% and 59.3%, respectively.
Study CLL3011: A randomized, open-label, Phase 3 study of Ibrutinib (Imbruvica) in combination with venetoclax versus chlorambucil in combination with obinutuzumab, was conducted in patients with previously untreated CLL or SLL who were 65 years or older, and adult patients <65 years of age with a CIRS score >6 or CrCL ≥30 to <70 mL/min. Patients with del 17p or known TP53 mutations were excluded. Patients (n=211) were randomized 1:1 to receive either Ibrutinib (Imbruvica) in combination with venetoclax or chlorambucil in combination with obinutuzumab. Patients in the Ibrutinib (Imbruvica) plus venetoclax arm received single agent Ibrutinib (Imbruvica) for 3 cycles followed by Ibrutinib (Imbruvica) in combination with venetoclax for 12 cycles (including 5-week dose ramp-up). Each cycle was 28 days. Ibrutinib (Imbruvica) was administered at a dose of 420 mg daily. Venetoclax was administered daily, starting with 20 mg for 1 week, followed by 1 week at each dose level of 50 mg, 100 mg, and 200 mg, then the recommended daily dose of 400 mg. Patients randomized to the chlorambucil plus obinutuzumab arm received treatment for 6 cycles. Obinutuzumab was administered at a dose of 1000 mg on Days 1, 8 and 15 in Cycle 1. In Cycles 2 to 6, 1000 mg obinutuzumab was given on Day 1. Chlorambucil was administered at a dose of 0.5 mg/kg body weight on Days 1 and 15 of Cycles=1 to 6. Patients with confirmed progression by IWCLL criteria after completion of either fixed duration regimen could be treated with single-agent Ibrutinib (Imbruvica).
The median age was 71 years (range, 47 to 93 years), 58% were male, and 96% were Caucasian. All patients had a baseline ECOG performance status of 0 (35%), 1 (53%), or 2 (12%). The trial enrolled 197 patients with CLL and 14 patients with SLL. At baseline, 18% of patients presented with CLL/SLL with del 11q and 52% with unmutated IGHV. The most common reasons for initiating CLL therapy included: constitutional symptoms (59%), progressive marrow failure (48%), lymphadenopathy (36%), splenomegaly (28%) and progressive lymphocytosis (19%). At baseline assessment for risk of tumor lysis syndrome, 25% of patients had high tumor burden. After 3 cycles of single-agent Ibrutinib (Imbruvica) lead-in therapy, 2% of patients had high tumor burden. High tumor burden was defined as any lymph node ≥10 cm; or any lymph node ≥5 cm and absolute lymphocyte count ≥25×10
9/L.
With a median follow-up time on study of 28 months, efficacy results for Study CLL3011 assessed by an IRC according to IWCLL criteria are shown in Table 10, the Kaplan-Meier curve for PFS is shown in Figure 9, and rates of minimal residual disease (MRD) negativity are shown in Table 11. (See Table 10 and Figure 9.)
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Click on icon to see table/diagram/image
The treatment effect of Ibrutinib (Imbruvica) plus venetoclax was consistent across the high-risk CLL/SLL population (TP53 mutation, del 11q, or unmutated IGHV), with a PFS HR of 0.23 [95% CI (0.13, 0.41)].
With a median follow-up of 28 months, overall survival data were not mature with a total of 23 deaths: 11 (10.4%) in the Ibrutinib (Imbruvica) plus venetoclax arm and 12 (11.4%) in the chlorambucil plus obinutuzumab arm. (See Table 11.)
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At three months after completion of treatment, 56 patients in Ibrutinib (Imbruvica) plus venetoclax arm who were MRD negative in peripheral blood by NGS assay had matched bone marrow specimens; of these, 52 patients (92.9%) were MRD negative in both peripheral blood and bone marrow.
Twelve months after the completion of treatment, MRD negativity rates in peripheral blood were 49.1% (52/106) by NGS assay and 54.7% (58/106) by flow cytometry in patients treated with Ibrutinib (Imbruvica) plus venetoclax and, at the corresponding time point, was 12.4% (13/105) by NGS assay and 16.2% (17/105) by flow cytometry in patients treated with chlorambucil plus obinutuzumab.
TLS was reported in 6 patients treated with chlorambucil plus obinutuzumab and no TLS was reported in Ibrutinib (Imbruvica) in combination with venetoclax.
Patients with CLL/SLL who received at least one prior therapy: Single agent: PCYC-1102-CA: An open-label, multi-center study was conducted in 51 patients with CLL/SLL, who received 420 mg once daily. Ibrutinib (Imbruvica) was administered until disease progression or unacceptable toxicity. The median age was 68 (range, 37 to 82 years), median time since diagnosis was 80 months, and median number of prior treatments was 4 (range, 1 to 12 treatments), including 92% with a prior nucleoside analog, 98.0% with prior rituximab, 86% with a prior alkylator, 39% with prior bendamustine and 20% with prior ofatumumab. At baseline, 39% of patients had Rai Stage IV, 45% had bulky disease (≥5 cm), 35% had del 17p, 31% had del 11q.
ORR was assessed according to the 2008 International Workshop on CLL (IWCLL) criteria. At a median duration follow up of 16 months, responses to Ibrutinib (Imbruvica) for the 51 patients are shown in Table 12. (See Table 12.)
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The efficacy data were further evaluated using IWCLL criteria by an IRC, demonstrating an ORR of 65% (95% CI: 50%; 78%), all partial responses. The DOR ranged from 4 to 24+ months. The median DOR was not reached.
PCYC-1112-CA: A randomized, multi-center, open-label phase 3 study of Ibrutinib (Imbruvica) versus ofatumumab was conducted in patients with CLL/SLL. Patients (n=391) were randomized 1:1 to receive either Ibrutinib (Imbruvica) 420 mg daily until disease progression or unacceptable toxicity, or ofatumumab for up to 12 doses (300/2000 mg). Fifty-seven patients randomized to ofatumumab crossed over following progression to receive Ibrutinib (Imbruvica). The median age was 67 years (range, 30 to 88 years), 68% were male, and 90% were Caucasian. All patients had a baseline ECOG performance status of 0 or 1. The median time since diagnosis was 91 months and the median number of prior treatments was 2 (range, 1 to 13 treatments). At baseline, 58% of patients had at least one tumor ≥5 cm. Thirty-two percent of patients had deletion 17p (with 50% of patients having deletion 17p/TP53 mutation), 24% had 11q deletion and 47% of patients had unmutated IGHV.
Progression-free survival (PFS) as assessed by an IRC according to IWCLL criteria indicated a 78% statistically significant reduction in the risk of death or progression for patients in the Ibrutinib (Imbruvica) arm. The results from investigator and IRC assessments for PFS were consistent. Analysis of overall survival (OS) demonstrated a 57% statistically significant reduction in the risk of death for patients in the Ibrutinib (Imbruvica) arm. Efficacy results for Study PCYC-1112-CA are shown in Table 13. (See Table 13.)
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The efficacy was similar across all of the subgroups examined, including in patients with and without deletion 17p, a pre-specified stratification factor (Figure 10). (See Figure 10.)
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The Kaplan-Meier curves for PFS and OS are shown in Figures 11 and 12, respectively. (See Figures 11 and 12.)
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Final Analysis at 65-month Follow-up: With median follow-up time on study of 65 months in Study PCYC-1112-CA, an 85% reduction in the risk of death or progression by investigator assessment was observed for patients in the Ibrutinib (Imbruvica) arm. The median investigator-assessed PFS according to IWCLL criteria was 44.1 months [95% CI (38.47, 56.18)] in the Ibrutinib (Imbruvica) arm and 8.1 months [95% CI (7.79, 8.25)] in the ofatumumab arm, respectively; HR=0.15 [95% CI (0.11, 0.20)]. The updated Kaplan-Meier curve for PFS is shown in Figure 13. The investigator-assessed ORR in the Ibrutinib (Imbruvica) arm was 87.7% versus 22.4% in the ofatumumab arm. At the time of final analysis, 133 (67.9%) of the 196 subjects originally randomized to the ofatumumab treatment arm had crossed over to ibrutinib treatment. The median investigator-assessed PFS2 (time from randomization until PFS event after first subsequent anti-neoplastic therapy) according to IWCLL criteria was 65.4 months [95% CI (51.61, not estimable)] in the Ibrutinib (Imbruvica) arm and 38.5 months [95% CI (19.98, 47.24)] in the ofatumumab arm, respectively; HR=0.54 [95% CI (0.41, 0.71)]. The median OS was 67.7 months [95% CI (61.0, not estimable)] in the Ibrutinib (Imbruvica) arm.
The treatment effect of ibrutinib in Study PCYC-1112-CA was consistent across high-risk patients with del 17p/TP53 mutation, del 11q, and/or unmutated IGHV. (See Figure 13.)
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CLL/SLL with deletion 17p: Study PCYC-1112-CA included 127 patients with CLL/SLL with deletion 17p. The median age was 67 years (range, 30 to 84 years), 62% were male, and 88% were Caucasian. All patients had a baseline ECOG performance status of 0 or 1. PFS and ORR were assessed by IRC. Efficacy results for CLL/SLL with deletion 17p are shown in Table 14. (See Table 14.)
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Overall follow-up of 63 months (median of 56 months): With an overall follow-up of 63 months (median of 56 months) in Study PCYC-1112-CA, the median investigator-assessed PFS in patients with del 17p according to IWCLL criteria was 40.6 months [95% CI (25.36, 44.55)] in the Ibrutinib (Imbruvica) arm and 6.2 months [95% CI (4.63, 8.11)] in the ofatumumab arm, respectively; HR=0.12, ([95% CI (0.07, 0.21)]. The investigator-assessed ORR in patients with del 17p in the Ibrutinib (Imbruvica) arm was 88.9% versus 18.8% in the ofatumumab arm.
Combination therapy: Study CLL3001: The safety and efficacy of Ibrutinib (Imbruvica) in patients previously treated for CLL/SLL were further evaluated in a randomized, multicenter, double-blinded phase 3 study of Ibrutinib (Imbruvica) in combination with BR versus placebo + BR. Patients (n=578) were randomized 1:1 to receive either Ibrutinib (Imbruvica) 420 mg daily or placebo in combination with BR until disease progression, or unacceptable toxicity. All patients received BR for a maximum of six 28-day cycles. Bendamustine was dosed at 70 mg/m
2 infused IV over 30 minutes on Cycle 1, Days 2 and 3, and on Cycles 2-6, Days 1 and 2 for up to 6 cycles. Rituximab was administered at a dose of 375 mg/m
2 in the first cycle, Day 1, and 500 mg/m
2 Cycles 2 through 6, Day 1. Ninety patients randomized to placebo + BR crossed over to receive Ibrutinib (Imbruvica) following IRC confirmed progression. The median age was 64 years (range, 31 to 86 years), 66% were male, and 91% were Caucasian. All patients had a baseline ECOG performance status of 0 or 1. The median time since diagnosis was 5.9 years and the median number of prior treatments was 2 (range, 1 to 11 treatments). At baseline, 56% of patients had at least one tumor ≥5 cm, 26% presented with del11q, and 72% had unmutated IGHV.
Progression free survival (PFS) was assessed by IRC according to IWCLL criteria indicated an 80% statistically significant reduction in the risk of death or progression. Efficacy results for Study CLL3001 are shown in Table 15 and the Kaplan-Meier curve for PFS is shown in Figure 14. (See Table 15 and Figure 14.)
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Waldenström's macroglobulinemia (WM): The safety and efficacy of Ibrutinib (Imbruvica) in WM (IgM-excreting lymphoplasmacytic lymphoma) were evaluated in one single-arm and one randomized, controlled study.
Study PCYC-1118E: An open-label, multi-center, single-arm trial (PCYC-1118E) was conducted in 63 previously-treated patients. The median age was 63 years (range, 44 to 86 years), 76% were male, and 95% were Caucasian. All patients had a baseline ECOG performance status of 0 or 1. The median time since diagnosis was 74 months, and the median number of prior treatments was 2 (range, 1 to 11 treatments). At baseline, the median serum IgM value was 3.5 g/dL (range, 0.7 to 8.4 g/dL), and 60% of patients were anemic (hemoglobin ≤11 g/dL).
Ibrutinib (Imbruvica) was administered orally at 420 mg once daily until disease progression or unacceptable toxicity. The primary endpoint in this study was ORR per investigator assessment. The ORR and DOR were assessed using criteria adopted from the Third International Workshop of Waldenström's Macroglobulinemia. Responses to Ibrutinib (Imbruvica) are shown in Table 16. (See Table 16.)
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The median time to response was 1.0 month (range, 0.7-13.4 months).
Efficacy results were also assessed by an IRC demonstrating an ORR of 82.5%, with a 11% VGPR rate and a 51% PR rate.
Study PCYC-1127-CA: A randomized, multicenter, double-blinded phase 3 study of Ibrutinib (Imbruvica) in combination with rituximab versus placebo in combination with rituximab (PCYC-1127-CA) was conducted in patients with treatment-naïve or previously treated WM. Patients (n=150) were randomized 1:1 to receive either IMBRUVICA 420 mg daily or placebo in combination with rituximab until disease progression or unacceptable toxicity. Rituximab was administered weekly at a dose of 375 mg/m
2 for 4 consecutive weeks (weeks 1-4) followed by a second course of weekly rituximab for 4 consecutive weeks (weeks 17-20).
The median age was 69 years (range, 36 to 89 years), 66% were male, and 79% were Caucasian. Ninety-three percent of patients had a baseline ECOG performance status of 0 or 1, and 7% of patients had a baseline ECOG performance status of 2. Forty-five percent of patients were treatment-naïve, and 55% of patients were previously treated. The median time since diagnosis was 52.6 months (treatment-naïve patients=6.5 months and previously treated patients=94.3 months). Among previously treated patients, the median number of prior treatments was 2 (range, 1 to 6 treatments). At baseline, the median serum IgM value was 3.2 g/dL (range, 0.6 to 8.3 g/dL), 63% of patients were anemic (hemoglobin ≤11 g/dL) and MYD88 L265P mutations were present in 77% of patients, absent in 13% of patients, and 9% of patients were not evaluable for mutation status.
Progression free survival (PFS) as assessed by IRC indicated an 80% statistically significant reduction in the risk of death or progression. Efficacy results for Study PCYC-1127-CA are shown in Table 17 and the Kaplan-Meier curve for PFS is shown in Figure 15. PFS hazard ratios for treatment-naïve patients, previously treated patients, and patients with or without MYD88 L265P mutations were consistent with the PFS hazard ratio for the ITT population. (See Table 17 and Figure 15.)
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Tumor flare in the form of IgM increase occurred in 8.0% of subjects in the Ibrutinib (Imbruvica) + rituximab arm and 46.7% of subjects in the placebo + rituximab arm.
63-Month Follow-Up (Final Analysis): With an overall follow-up of 63 months, efficacy results as assessed by an IRC at the time of the final analysis for PCYC-1127-CA are shown in Table 18. PFS hazard ratios for treatment-naïve patients (0.31 [95% CI (0.14, 0.69)]) and previously treated patients (0.22 [95% CI (0.11, 0.43)]) were consistent with the PFS hazard ratio for the ITT population. (See Table 18.)
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Study PCYC-1127-CA had a separate monotherapy arm of 31 patients with previously treated WM who failed prior rituximab-containing therapy and received single agent Ibrutinib (Imbruvica). The median age was 67 years (range, 47 to 90 years). Eighty-one percent of patients had a baseline ECOG performance status of 0 or 1, and 19% had a baseline ECOG performance status of 2. The median number of prior treatments was 4 (range, 1 to 7 treatments). The response rate per IRC observed in the monotherapy arm was 71% (0% CR, 29% VGPR, 42% PR). The overall response rate per IRC observed in the monotherapy arm was 87% (0% CR, 29% VGPR, 42% PR, 16% MR). With a median follow-up time on study of 34 months (range, 8.6+ to 37.7 months), the median duration of response has not been reached.
61-Month Follow-Up (Final Analysis): With an overall follow-up of 61 months, the response rate observed in Study PCYC-1127-CA monotherapy arm per IRC assessment was 77% (0% CR, 29% VGPR, 48% PR). The median duration of response was 33 months (range, 2.4 to 60.2+ months). The overall response rate per IRC observed in the monotherapy arm was 87% (0% CR, 29% VGPR, 48% PR, 10% MR). The median duration of overall response was 39 months (range, 2.07 to 60.2+ months).
Pharmacokinetics: Absorption: Ibrutinib is rapidly absorbed after oral administration with a median T
max of 1 to 2 hours. Absolute bioavailability in fasted condition (n=8) was 2.9% (90% CI=2.1-3.9) and doubled when combined with a meal. Pharmacokinetics of ibrutinib does not significantly differ in patients with different B‑cell malignancies. Ibrutinib exposure increases with doses up to 840 mg. The steady state AUC observed in patients at 560 mg is (mean ± standard deviation) 953 ± 705 ng·h/mL and in patients at 420 mg with CLL/SLL is 732 ± 521 ng·h/mL (680 ± 517 ng·h/mL in subset of R/R patients) and with cGVHD is 1159 ± 583 ng·h/mL. Administration of ibrutinib in fasted condition resulted in approximately 60% of exposure (AUC
last) as compared to either 30 minutes before, 30 minutes after (fed condition) or 2 hours after a high fat breakfast.
Distribution: Reversible binding of ibrutinib to human plasma protein
in vitro was 97.3% with no concentration dependence in the range of 50 to 1,000 ng/mL. The volume of distribution (V
d) was 683 L and the apparent volume of distribution at steady state (V
d,ss/F) was approximately 10,000 L.
Metabolism: Ibrutinib is metabolized primarily by cytochrome P450, CYP3A4/5 to produce a prominent dihydrodiol metabolite with an inhibitory activity towards BTK approximately 15 times lower than that of ibrutinib. Systemic steady-state exposure to the dihydrodiol metabolite is comparable to that of the parent drug.
In vitro studies indicated that CYP2D6 involvement in ibrutinib oxidative metabolism is <2%. Moreover, as part of the human mass balance study, subjects genotyped as poor metabolizers for CYP2D6, showed a similar pharmacokinetic profile as extensive metabolizers. Therefore, no precautions are necessary in patients with different CYP2D6 genotypes.
Elimination: Intravenous clearance was 62 and 76 L/h in fasted and fed condition, respectively. In line with the high first-pass effect, the apparent oral clearance is approximately 2,000 and 1,000 L/h in fasted and fed condition, respectively. The half-life of ibrutinib is 4 to 6 hours.
After a single oral administration of radiolabeled [
14C]‑ibrutinib in healthy subjects, approximately 90% of radioactivity was excreted within 168 hours, with the majority (80%) excreted in the feces and <10% accounted for in urine. Unchanged ibrutinib accounted for approximately 1% of the radiolabeled excretion product in feces and none in urine, with the remainder of the dose being metabolites.
Special populations: Elderly (65 years of age and older): Population pharmacokinetics indicated that in older patients (67 to 81 years), a 14% higher ibrutinib exposure is predicted. Dose adjustment by age is not warranted.
Pediatric population (18 years of age and younger): No pharmacokinetic studies were performed with Ibrutinib (Imbruvica) in patients under 18 years of age.
Gender: Population pharmacokinetics data indicated that gender does not significantly influence ibrutinib clearance from the circulation.
Renal impairment: Ibrutinib has minimal renal clearance; urinary excretion of metabolites is <10% of the dose. No specific studies have been conducted to date in subjects with impaired renal function. No dose adjustment is needed for patients with mild or moderate renal impairment (greater than 30 mL/min creatinine clearance). There are no data in patients with severe renal impairment or patients on dialysis.
Hepatic impairment: Ibrutinib is metabolized in the liver. A hepatic impairment trial was performed in non-cancer subjects administered a single dose of 140 mg of Ibrutinib (Imbruvica) under fasting conditions. Ibrutinib AUC
last increased 2.7-, 8.2-, and 9.8-fold in subjects with mild (n=6, Child-Pugh class A), moderate (n=10, Child-Pugh class B) and severe (n=8, Child-Pugh class C) hepatic impairment, respectively. The free fraction of ibrutinib also increased with degree of impairment, with 3.0, 3.8 and 4.8% in subjects with mild, moderate and severe liver impairment, respectively, compared to 3.3% in plasma from matched healthy controls within this study. The corresponding increase in unbound ibrutinib exposure (AUC
unbound,
last) is estimated to be 4.1-, 9.8-, and 13-fold in subjects with mild, moderate, and severe hepatic impairment, respectively.
Toxicology: Non-Clinical Information: The following adverse effects were seen in studies of 13-weeks duration in rats and dogs. Ibrutinib was found to induce gastrointestinal effects (soft feces/diarrhea and/or inflammation) and lymphoid depletion in rats at human equivalent doses (HEDs) ≥16 mg/kg/day and dogs at HEDs ≥32 mg/kg/day. Effects on lymphoid tissue (lymphoid depletion) were also induced at HEDs ≥28 mg/kg/day in rats and ≥32 mg/kg/day in dogs. In rats, moderate pancreatic acinar cell atrophy was observed at HEDs ≥6 mg/kg/day. Mildly decreased trabecular and cortical bone was seen in rats administered HEDs ≥16 mg/kg/day for 13 weeks. All notable findings in rats and dogs fully or partially reversed following recovery periods of 6 to 13 weeks.
Carcinogenicity and Mutagenicity: Ibrutinib was not carcinogenic in a 6-month study in the transgenic (Tg.rasH2) mouse at oral doses up to 2,000 mg/kg/day resulting in exposures approximately 23 (males) to 37 (females) times higher than the exposure in humans at a dose of 560 mg daily.
Ibrutinib has no genotoxic properties when tested in bacteria, mammalian cells or in mice.
Fertility: No effects on fertility or reproductive capacities were observed in male or female rats up to the maximum dose tested, 100 mg/kg/day (HED 16 mg/kg/day).
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