On December 10, 2018 Janssen Pharmaceutical Companies of Johnson & Johnson reported new findings from three key studies on IMBRUVICA (ibrutinib) in the treatment of chronic lymphocytic leukemia (CLL), a difficult-to-treat form of blood cancer and cancer most common form of leukemia in adults (Press release, Johnson & Johnson, DEC 10, 2018, View Source [SID1234531992]). 1 The findings were presented at the 60th Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper), held in San Diego, California.
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The results of the National Cancer Institute’s (NCI) funded Phase III study (E1912) led by the ECOG-ACRIN Cancer Research Group (ECOG-ACRIN) were presented during the late-breaker lecture series. The study evaluated doses of ibrutinib plus rituximab compared to chemotherapy with fludarabine, cyclophosphamide, and rituximab (FCR) from previously untreated CLL patients aged 70 years or younger. In a three-year follow-up study, data for ibrutinib plus rituximab showed significantly prolonged progression-free survival (PFS) and overall survival (OS) compared to FCR. 2
The data from the Phase III iLLUMINATE (PCYC-1130) study were also published in a lecture series and at the same time in the journal The Lancet Oncology . The results showed significantly prolonged progression-free survival in patients taking newly diagnosed CLL in additions of ibrutinib plus obinutuzumab compared with chlorambucil plus obinutuzumab. 3 These data recently supported the submission of an application for Type II amendments to the European Medicines Agency (EMA) to request the approval of extended use of ibrutinib in combination with obinutuzumab in previously untreated CLL patients.
In addition, data from the Phase Ib / II study and its extension study (PCYC-1102, PCYC-1103) in patients with newly diagnosed and relapsed / refractory (r / r) CLL and monotherapy showed up to seven years of follow-up the lasting long-term improvements in progression-free survival. This was the longest follow-up study to treat CLL with the Bruton tyrosine kinase (BTK) inhibitor. 4
"The results of both the iLLUMINATE and the ECOG-ACRIN study show an impressive prolongation of progression-free survival for the relevant ibrutinib-based combinations compared to commonly used chemo-immunotherapies," Dr. Carol Moreno, Haematologist Consultant, Santa Creu Hospital Sant Pau, Autonomous University of Barcelona, Barcelona (Spain). "These non-chemotherapies represent progress in the way we consider caring for patients, including younger patients and those with high-risk CLL characteristics, with the potential to help overcome the conflict of interest between patient efficacy and toxicity . "
"The data provided by ASH (Free ASH Whitepaper) demonstrate the clinical benefit of ibrutinib for CLL patients across the full spectrum of treatment. The long-term data also conveys confidence in the sustainable activities for the benefit of the patients, "Dr. Catherine Taylor, Haematology Therapy Area Lead, Europe, Middle East and Africa (EMEA), Janssen-Cilag Limited. "We continue to explore the full potential of ibrutinib as part of a comprehensive clinical development program to improve outcomes and bring about changes in the importance of blood cancer diagnosis for patients."
Ibrutinib, a first-in-class BTK inhibitor, is being developed and marketed jointly by Janssen Biotech, Inc. and Pharmacyclics LLC, an AbbVie company.
Results of the randomized Phase III study of ibrutinib (PCI-32765) -based treatment versus FCR chemo-immunotherapy of untreated younger patients with CLL: A study by the ECOG-ACRIN Cancer Research Group (E1912) ( Abstract LBA -4 )
In a mean follow-up of 33.4 months, the interim analysis found 77 PFS events (progression-free survival) and 14 deaths. Ibrutinib plus rituximab significantly improved PFS events compared to FCR (hazard ratio (HR): 0.352; 95% confidence interval [CI]: 0.233-0.558; p <0.0001). The predetermined limit for progression-free life has been exceeded. Treatment with ibrutinib plus rituximab also showed improvement in overall survival (OS) (HR: 0.168, 95% CI: 0.053-0.538, p = 0.0003, predetermined superiority limit p = 0.0005). 2
In a PFS subgroup analysis, treatment with ibrutinib plus rituximab showed PFS prolongation, regardless of age, sex, ability, stage of disease or presence / absence of a cytogenetic abnormality (11q23 deletion). In the current follow-up study, treatment with ibrutinib plus rituximab also demonstrated superiority over FCR in patients without IGHV mutation (HR: 0.262, 95% CI: 0.137-0.498, p <0.0001) but without IGHV mutation (HR : 0.435, 95% CI: 0.140-0.1350, p = 0.07). 2
Grade 3/4 treatment-related adverse events were observed in 58% of ibrutinib plus rituximab-treated patients and 72% of FCR-treated patients (p = 0.0042). FCR levels were more common with grade 3 or 4 neutropenia (FCR: 44% compared to ibrutinib plus rituximab: 23%, p <0.0001) and infectious complications (FCR: 17.7% compared to ibrutinib plus rituximab: 7.1%; p <0.0001). 2
Results of the Phase III iLLUMINATE Study ( Abstract # 691 )
In a median follow-up period of 31.3 months, progression-free survival was prolonged when irrigation with ibrutinib plus obinutuzumab was evaluated by the Independent Review Committee (IRC) compared with chlorambucil plus obinutuzumab (median not reached [NR] compared to 19 HR 0.231, 95% CI: 0.145-0.367, p <0.0001) with a 77% reduction in the risk of disease progression or risk of death. 3
A superiority in progression-free survival in treatment with ibrutinib plus obinutuzumab compared with chlorambucil plus obinutuzumab was also found in the high-risk population, including those without IGHV mutation, 11q deletion, 17p deletion and TP53 mutation, respectively with an 85% reduction in the risk of disease progression or mortality (median not reached [NR] compared to 14.7 months, HR 0.154, 95% CI: 0.087-0.270, p <0.0001). 5 In addition, the IRC-assessed overall response rate (ORR) was higher for the ibrutinib plus obinutuzumab-treated patients compared to chlorambucil plus obinutuzumab (88% vs. 73%); complete remission (CR rates) / complete remission with incomplete blood repair (CRi rates) was significantly higher at 19% compared to 8%. Minimal residual disease (MRD) could not be detected in the blood or bone marrow (<10 -4using flow cytometry) in 35% of patients treated with ibrutinib plus obinutuzumab compared with 25% of those treated with chlorambucil plus obinutuzumab. The overall survival rates at 30 months were 86% for patients treated with ibrutinib plus obinutuzumab compared to 85% for chlorambucil plus obinutuzumab. 3
The most common grade 3 or higher adverse events associated with ibrutinib plus obinutuzumab compared to chlorambucil plus obinutuzumab were neutropenia (36% versus 46%), thrombocytopenia (19% vs. 10%), pneumonia (7% vs. 4%), Atrial flutter (5% versus 0%), febrile neutropenia (4% vs. 6%), anemia (4% versus 8%) and infusion-related reactions (IRR, 2% versus 8%). 5No patient had to discontinue treatment with obinutuzumab due to infusion-related reactions in patients treated with ibrutinib plus obinutuzumab compared to chlorambucil plus obinutuzumab (6%). Adverse events caused discontinuation of ibrutinib treatment in 16% of patients and discontinuation of chlorambucil treatment in 9% of patients. Adverse events caused the discontinuation of obinutuzumab in treatment with ibrutinib plus obinutuzumab (13%) and chlorambucil plus obinutuzumab (13%). In a three-year follow-up study, 70% of patients who received ibrutinib plus obinutuzumab received ibrutinib monotherapy. 3
Outcome of up to seven years follow-up in the Phase Ib / II PCYC 1102 study and its extension PCYC-1103 ( Abstract # 3133 )
Results from these studies demonstrated continued efficacy of ibrutinib in newly diagnosed and r / r CLL patients. These long-term data showed sustained PFS and overall survival rates. The estimated seven-year PFS rates were 80% in patients with newly diagnosed disease and 32% in patients with r / r disease. In particular, the administration of ibrutinib in previous treatment lines resulted in better PFS treatment results in r / r patients. 4
The overall response rate was 89% for all patients (CR, 15%), with similar rates in newly diagnosed patients (87% [CR, 32%]) and r / r-CLL patients (89% [CR, 10%] , The mean duration of response (DOR) was NR (95% CI: 0 + -85 +) in newly diagnosed CLL patients and was 57 months (95% CI: 0 + -85 +) with r / r-CLL agency counted. 6 The PFS median score was NR (95% CI: unpredictable [NE], NE) for newly diagnosed patients and was 51 months (95% CI: 37-70) for r / r CLL patients. 4.6 Overall median survival was NR in newly diagnosed patients (95% CI: 80-NE) or r / r CLL patients (95% CI: 63-NE), with estimated seven-year overall survival rates of 75% and 75%, respectively. 52%. 4
Adverse events of grade 3 or higher were reported in 74% of newly diagnosed patients and 89% of r / r patients with CLL. Hypertension (newly diagnosed, 32%, r / r, 26%), diarrhea (newly diagnosed, 16%, r / r, 4%) and hyponatraemia (newly diagnosed, 10%, r / r, 0%) were among the most common therapy-related adverse events of grade 3 or higher. Severe hemorrhage and atrial flutter, thrombocytopenia, grade 3 anemia and arthralgia were seen in 11% or less of newly diagnosed and r / r patients. In addition, infections (newly diagnosed, 23%, r / r, 55%) were more common in r / r-CLL patients. 6No or unexpected adverse events were observed and the occurrence of these events of grade 3 or greater and serious adverse events increased with time (except high blood pressure). 6
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About the ECOG-ACRIN-E1912 study
The Phase III study (E1912) evaluated previously untreated patients with CLL aged 70 or younger who were randomly assigned to receive ibrutinib (420 mg / day to progression) and rituximab (50 mg / m) 2 on day 1 of cycle 2, 325 mg / m2 on day 2 of cycle 2, 500 mg / m2 on day 1 of cycles 3 to 7) (n = 354) or six intravenous administrations of fludarabine (25 mg / m) 2 (), and cyclophosphamide 250 mg / m 2 ) on days 1 to 3 (with rituximab 50 mg / m 2 on day 1 of cycle 1; 325 mg / m 2 on day 2 of cycle 1; 500 mg / m 2 on day 1 of cycles 2 to 6) every 28 days (n = 175). The primary endpoint was progression-free survival (PFS) and a secondary endpoint overall survival (OS). 2
The state-sponsored study was prepared by researchers in cooperation with ECOG-ACRIN. It was conducted by the National Clinical Trials Network of the NCI (National Cancer Institute). Pharmacyclics LLC provided Ibrutinib under an agreement for a research and development collaboration with the NCI and a separate agreement with ECOG-ACRIN.
About the iLLUMINATE study
iLLUMINATE ( PCYC-1130 ) evaluated patients with newly diagnosed CLL who were randomized to receive 420 mg ibrutinib once daily until disease progression or unacceptable toxicity or in combination with obinutuzumab 1000 mg intravenously for six cycles (n = 113); or chlorambucil on days 1 and 15 for each cycle plus 1000 mg of obinutuzumab administered intravenously over a period of 6 cycles (n = 116). The median age of the patients was 71 years and 65% of the patients had a high hazard potential for genomic characteristics. The primary endpoint was PFS, as assessed by the Independent Review Committee. The secondary endpoints were progression-free survival (PFS) in a high-risk population, the rate of undetectable MRD,3
About PCYC-1102 and PCYC-1103
In a follow-up study lasting up to seven years, the studies (Phase Ib / II, PCYC-1102 and their extension PCYC-1103 ) evaluated newly diagnosed and r / r-CLL patients (n = 132, newly diagnosed = 31, r / r = 101), including those with high-risk traits, who received 420 mg or 840 mg ibrutinib once daily until disease progression or unacceptable toxicity. By the cut-off date, 55% of the newly diagnosed and 21% of the r / r patients continued to receive ibrutinib with a median follow-up of 67 months. 4
About ibrutinib
Ibrutinib is a brutone tyrosine kinase (BTK) inhibitor, a first in this new class of drugs that works by building strong covalent binding with BTK, which blocks the transmission of cell survival signals to malignant B lymphocytes. 7 through blockade of the BTK protein Ibrutinib contributes to the destruction of these cancer cells and reduce their number. As a result, it slows the progression of the cancer. 8th
Ibrutinib is currently authorized in Europe for the following uses: 9
Chronic lymphocytic leukemia (CLL): As a single agent for the treatment of adult patients with previously untreated CLL and as a single agent or in combination with bendamustine and rituximab (BR) for the treatment of adult patients with CLL who have previously undergone at least one therapy.
Mantle Cell Lymphoma (MCL): Adult patients with relapsed or refractory mantle cell lymphoma.
Waldenstrom Macroglobulinemia (WM): Adult patients who have undergone at least one prior therapy or first-line treatment or first-line treatment of patients who are not eligible for chemo-immunotherapy.
Ibrutinib is approved in more than 90 countries and has been used to treat more than 135,000 patients around the world as part of its approved indications. 10
The most common adverse events with ibrutinib supplements include diarrhea, neutropenia, hemorrhage (eg bruises), musculoskeletal pain, nausea, rash, and pyrexia. 9
For a full list of adverse reactions and information on dosing and administration, contraindications and other precautions for use with Ibrutinib, see the Summary of Product Characteristics .