on December 7, 2018 Janssen Pharmaceutical Companies of Johnson & Johnson reported new results from three key studies on IMBRUVICA (ibrutinib) for Chronic Lymphocytic Leukemia (CLL), a form complex to treat blood cancer and the most common form of leukemia in adults (Press release, Johnson & Johnson, DEC 7, 2018, View Source [SID1234531955]). 1 The findings were presented at the 60 th Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) in San Diego, California.
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The results of the National Cancer Institute (NCI) Phase 3 study (E1912), led by the ECOG-ACRIN Cancer Research Group (ECOG-ACRIN), were presented during the oral session on last-minute abstracts . The study evaluated ibrutinib plus rituximab compared to a chemotherapy regimen with fludarabine, cyclophosphamide and rituximab (FCR) in previously untreated patients aged 70 years or less with CLL. With nearly three years of follow-up, data showed that ibrutinib plus rituximab significantly prolonged progression-free survival (PFS) and overall survival (OS) compared with CRF. 2
Phase III data from the iLLUMINATE (PCYC-1130) study were also presented at an oral session and published simultaneously in The Lancet Oncology . The findings showed that the combination of ibrutinib plus obinutuzumab significantly improved PFS compared with chlorambucil plus obinutuzumab in patients with newly diagnosed CLL. 3 These data have recently supported a request for Type II variation filed with the European Medicines Agency (EMA) and aimed at approval for the expanded use of ibrutinib in combination with obinutuzumab in adults not previously treated with
In addition, data on ibrutinib in the Phase 1b / 2 study and its extension study (PCYC-1102, PCYC-1103) with follow-up of up to 7 years in patients with CLL recently diagnosed recurrent / refractory (R / R) have demonstrated long-term, sustainable survival benefits in monotherapy, the longest follow-up for a Bruton tyrosine kinase (BTK) inhibitor in the treatment of an LLC. 4
"The results of the iLLUMINATE and ECOG-ACRIN studies demonstrate an impressive increase in progression-free survival for relevant ibrutinib-based combinations, compared to the commonly used chemo-immunotherapy protocols," says hematologist consultant Dr. Carol Moreno. at the Santa Creu Sant Pau Hospital, Autonomous University of Barcelona, Barcelona, Spain. "These chemotherapy-free protocols represent a breakthrough in our approach to treating patients, including young patients and those with high-risk CLL, with the potential to reach a compromise between efficacy and patient toxicity. . "
"The data presented at the ASH (Free ASH Whitepaper) provide convincing additional evidence of the clinical benefit that ibrutinib can provide to patients across all CLL therapies." Long-term data provide confidence for its prolonged activity for patients, "says Dr. Catherine Taylor, Head of Hematology Therapies for Europe, Middle East and Africa (EMEA) at Janssen-Cilag Limited. "We continue to explore the full potential of ibrutinib through a comprehensive clinical development program, to improve outcomes and change what a diagnosis of blood cancer can mean for patients."
Ibrutinib, a leading BTK inhibitor, is jointly developed and marketed by Janssen Biotech, Inc., and Pharmacyclics LLC, an AbbVie company.
Results of the Randomized Phase 3 Study of Ibrutinib-Based Therapy (PCI-32765) vs FCR Chemo-Immunotherapy in Young Untreated CLL Patients: An ECOG-ACRIN Cancer Study Research Group (E1912) ( Abstract No. LBA-4 )
With a median follow-up of 33.4 months, the interim analysis observed 77 PHC events and 14 deaths. Ibrutinib plus rituximab significantly improved PFS compared with RCF (RR 0.352, 95 percent confidence interval [CI] 0.223-0.558, p <0.0001); the pre-specified threshold for the SSP has been crossed. The ibrutinib plus rituximab group also showed an improvement in SG (RR: 0.168, 95 percent CI: 0.053-0.538, p = 0.0003, pre-specified threshold for superiority p = 0.0005). 2
In a subgroup analysis for PFS, ibrutinib plus rituximab showed lengthening of PFS regardless of age, gender, performance status, stage of illness, or presence / absence of the cytogenetic abnormality, deletion 11q23. According to current monitoring, ibrutinib plus rituximab was also superior to CRF for non-mutated IGHV patients (RR: 0.262, 95 percent CI 0.137-0.498, p <0.0001), but not IGHV patients mutated (RR 0.435, 95 percent CI 0.140-0.11350, p = 0.07). 2
Grade 3/4 treatment-related adverse events were observed in 58 percent of patients treated with ibrutinib plus rituximab, and 72 percent of patients treated with CRF (p = 0.0042). The RCF was more frequently associated with grade 3 and 4 neutropenia (RCF: 44 percent vs ibrutinib plus rituximab: 23 percent, p <0.0001) and infectious complications (RCF: 17.7 percent vs ibrutinib plus rituximab: 7.1 percent, p <0.0001). 2
Results of the iLLUMINATE Phase 3 study ( abstract n ° 691 )
At a median follow-up of 31.3 months, ibrutinib plus obinutuzumab had significantly lengthened the PFS assessed by an independent review committee (IRC), compared with chlorambucil plus obinutuzumab (mean unmet vs. 19.0 months; 0.231, 95 percent CI 0.145-0.367, p <0.0001), with a 77 percent reduction in the risk of progression or death. 3
A higher SSP in the ibrutinib plus obinutuzumab group, compared to the chlorambucil plus obinutuzumab group, was also observed in the high risk group, including in patients with IGHV, del11q, del17p non-mutated and / or TP53 mutation, with 85 percent reduction in risk of progression or death (mean not achieved vs. 14.7 months, RR 0.154, 95 percent CI: 0.087-0.270, p <0.0001). 5 In addition, the overall response rate (TRG) assessed by CEI was higher in the ibrutinib plus obinutuzumab group compared to the chlorambucil plus obinutuzumab group (88 percent vs. 73 percent); Complete response rates (CR) / complete response with incomplete blood recovery were also higher (19 percent vs. 8 percent, respectively). Minimal residual disease (MRM) was not detectable in the blood and / or bone marrow (<10 -4 by flow cytometry) for 35 percent of patients treated with ibrutinib plus obinutuzumab, compared to 25 percent of patients treated with chlorambucil plus obinutuzumab. The 30-month SG rates were 86 percent for the ibrutinib plus obinutuzumab group compared to 85 percent for the chlorambucil plus obinutuzumab group. 3
The most common grade 3 or higher adverse events in the ibrutinib plus obinutuzumab group, compared to the chlorambucil plusobinutuzumab group, were neutropenia (36 percent vs 46 percent), thrombocytopenia (19 percent vs. 10 percent) pneumonia (7 percent vs. 4 percent), atrial fibrillation (5 percent vs. 0 percent), febrile neutropenia (4 percent vs. 6 percent), anemia (4 percent vs. 8 percent), and perfusion (PRP, 2 percent vs 8 percent). 5No patients stopped taking obinutuzumab because of RLP in the ibrutinib plus obinutuzumab group, compared to the chlorambucil plus obinutuzumab group (6 percent). Adverse events led to discontinuation of ibrutinib in 16 percent of patients, and discontinuation of chlorambucil in nine percent of patients. Adverse events led to discontinuation of obinutuzumab in the ibrutinib plus obinutuzumab group (9 percent) and in the chlorambucil plus obinutuzumab group (13 percent). With approximately three years of follow-up, 70 percent of patients in the ibrutinib plus obinutuzumab group continue ibrutinib monotherapy. 3
Follow-up Results to Seven Years in PCYC-1102 Phase 1b / 2 and its Extension Study, PCYC-1103 ( Abstract # 3133 )
The results of these studies demonstrated the sustained efficacy of ibrutinib in patients with newly diagnosed R / R LLC. These long-term data showed prolonged PHC and OS. The estimated seven-year PHC rates were 80 percent for patients with newly diagnosed disease and 32 percent for patients with R / R disease. It should be noted that earlier administration of ibrutinib in the therapeutic lines resulted in an improvement in SSP for R / R patients. 4
The TRG was 89 percent for all patients (RC, 15 percent), with similar rates in newly diagnosed patients (87 percent [RC, 32 percent]) and R / R LLC patients (89 percent). cent [RC, 10 percent]). The median response time (DR) was not reached (95 percent CI: 0 + -85 +) for newly diagnosed CLL patients and was 57 months (95 percent CI: 0 + – 85+) for R / R LLC patients. 6 Median PFS was not achieved (95 percent CI: not estimable [NE], NE) for newly diagnosed CLL patients, and 51 months (95 percent CI 37-70) for R / R LLC patients. 4.6Median OS was not affected in newly diagnosed patients (95 percent of IC: 80-NE) or in R / R LLC patients (95 percent of IC: 63-NE), with seven-year GS estimates of 75 percent and 52 percent, respectively. 4
Grade 3 or higher adverse events were reported in 74 percent of newly diagnosed patients and 89 percent of R / R LLC patients. Of the Grade 3 or higher adverse events that occurred during treatment, the most common were: hypertension (newly diagnosed, 32 percent, R / R, 26 percent), diarrhea (newly diagnosed, 16 percent, R / R , 4 percent), and hyponatraemia (newly diagnosed, 10 percent, R / R, 0 percent). Cases of major bleeding and atrial fibrillation, thrombocytopenia, anemia, and grade 3 or greater arthralgia have been observed in 11 percent or less of newly diagnosed patients and R / R patients. In addition, the cases of6 No new or unexpected adverse events were observed, and the occurrence of most grade 3 or higher adverse events and serious adverse events decreased over time, with the exception of hypertension. 6
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About the ECOG-ACRIN E1912 study
The Phase 3 study (E1912) evaluated previously untreated CLL patients aged 70 years or less who were randomized to receive ibrutinib (420 mg / day until disease progression) and rituximab (50 mg / m 2 at day 1 of cycle 2, 325 mg / m 2 at day 2 of cycle 2, 500 mg / m 2 at day 1 of cycles 3-7) (n = 354) or six series intravenous fludarabine (25 mg / m 2 ) and cyclophosphamide (250 mg / m 2 ) on days 1-3 with rituximab (50 mg / m 2 on day 1 of cycle 1, 325 mg / m 2 on day 2 Cycle 1, 500 mg / m 2at day 1 of cycles 2-6) every 28 days (n = 175). The main criterion was SSP, with the SG as a secondary criterion. 2
From federal funding, the study was designed by ECOG-ACRIN researchers. It was conducted via NCI’s national clinical trial network. Pharmacyclics LLC provided ibrutinib as part of a cooperative research and development agreement with the NCI and a separate agreement with ECOG-ACRIN.
About the iLLUMINATE study
The iLLUMINATE study ( PCYC-1130 ) evaluated patients with newly diagnosed CLL who were randomized to receive ibrutinib 420 mg once daily continuously until disease progression or unacceptable toxicity in combination with obinutuzumab 1000 mg intravenous for six cycles (n = 113); or chlorambucil on days 1 and 15 of each cycle plus obinutuzumab 1000 mg intravenously for 6 cycles (n = 116). The median age of the patients was 71 years and 65 percent of the patients had high risk genomic characteristics. The primary criterion was SSP, as assessed by an independent review committee. Secondary endpoints included PHC in a high-risk population,3
About PCYC-1102 and PCYC-1103 studies
With follow-up up to seven years, studies (Phase 1b / 2, PCYC-1102 and its extension study, PCYC-1103 ) evaluated patients with newly diagnosed R / R CLL (n = 132; diagnosed = 31, R / R = 101), including patients with high-risk characteristics, who received 420 mg or 840 mg ibrutinib once daily until disease progression or unacceptable toxicity. At the cutoff date, 55 percent of newly diagnosed patients and 21 percent of R / R patients had continued ibrutinib, with a median follow-up of 67 months. 4
About ibrutinib
Ibrutinib is a first-of-its-kind Bruton tyrosine kinase inhibitor (BTK), which acts as a strong covalent bond to BTK to block the transmission of cell survival signals into malignant B-cells. 7 By blocking this BTK protein, ibrutinib helps kill and reduce the number of cancer cells, thus delaying cancer progression. 8
The Ibrutinib is currently approved in Europe for the following uses: 9
Chronic Lymphocytic Leukemia (CLL): as a single agent in the treatment of adult patients with previously untreated CLL, and as a single agent or in combination with bendamustine plus rituximab (BR) for treatment adult patients with CLL who have received at least one therapy.
Mantle lymphoma: adult patients with recurrent or refractory mantle cell lymphoma.
Waldenström Macroglobulinemia (WM): Adult patients who have received at least one therapy or first-line treatment for patients not eligible for chemo-immunotherapy.
Ibrutinib is approved in more than 90 countries and has been used to date to treat more than 135,000 patients worldwide on all of its approved indications. 10
The most common adverse reactions observed with ibrutinib were: diarrhea, neutropenia, hemorrhage (eg bruising), musculoskeletal pain, nausea, rash, and pyrexia. 9
For a complete list of side effects and for information on dosage and administration, contraindications and other precautions on the use of ibrutinib, please refer to the summary of product characteristics .