On December 7, 2018 Johnson & Johnson Janssen pharmaceutical companies reported new results from three important studies on IMBRUVICA (ibrutinib) in chronic lymphocytic leukemia (CLL), a form of difficult blood cancer treatment as well as the most common type of leukemia in adults (Press release, Johnson & Johnson, DEC 7, 2018, View Source [SID1234531954]). 1 The results were presented during the 60th annual congress of the American Society of Hematology (ASH) (Free ASH Whitepaper) in San Diego, California.
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The results of the Phase 3 study (E1912) sponsored by the National Cancer Institute (NCI) and led by the ECOG-ACRIN Cancer Research Group (ECOG-ACRIN) were presented during the oral session dedicated to abstracts late breakers. The study evaluated ibrutinib in combination with rituximab compared to a chemotherapy regimen with fludarabine, cyclophosphamide, and rituximab (FCR) in previously untreated CLL patients younger than 70 years. Following a nearly 3-year follow-up, these data showed that the combination of ibrutinib plus rituximab significantly prolonged progression-free survival (PFS) and overall survival (OS) compared to FCR. 2
Data from the iLLUMINATE phase 3 study (PCYC-1130) were also presented during an oral session, with concurrent publication in The Lancet Oncology . The results show that the combination of ibrutinib and obinutuzumab significantly improves PFS compared to chlorambucil and obinutuzumab in recently diagnosed CLL patients. 3 These data recently supported the submission of a Type 2 variation application to the European Medicines Agency (EMA) to request authorization for the extended use of ibrutinib in combination with obinutuzumab in previously untreated CLL adults.
Data from the 1b / 2 hybridutinib study and the related extension study (PCYC-1102, PCYC-1103) with a follow-up of up to seven years on newly diagnosed relapsed / refractory (R / R) CLL patients they also demonstrated long-term and long-term survival benefits following monotherapy treatment, and constitute the longest follow-up for a Bruton tyrosine kinase (BTK) inhibitor in CLL. 4
"The results of iLLUMINATE and ECOG-ACRIN studies demonstrate an extremely prolonged progression-free survival for the relative combinations based on ibrutinib compared to commonly used chemo-immunotherapy regimens," said Dr. Carol Moreno, Hematology Consultant at Hospital de the Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain. "These non-chemotherapeutic regimens are a step forward in assessing how patients are treated, including the younger ones and with high-risk CLL, and offer the potential to resolve the compromise between efficacy and toxicity for patients."
"The data presented at the INA congress provide a further and convincing evidence of the clinical benefits that ibrutinib can offer to patients across the spectrum of CLL management." Long-term data are also promising in terms of long-term found for patients, "said Dr. Catherine Taylor, head of the hematology area for the EMEA region (Europe, Middle East and Africa) of Janssen-Cilag Limited. "We continue to study the full potential of ibrutinib with a comprehensive clinical development program, to improve results and modify the consequences of diagnosing blood cancer for patients."
Ibrutinib, a first class BTK inhibitor, is developed and marketed jointly by Janssen Biotech, Inc., and Pharmacyclics LLC, an AbbVie company.
Results of the Randomized Phase 3 Study on Hybridinib (PCI-32765) Therapy vs. FCR Chemo-Immunotherapy in Untreated Young CLL Patients: an ECOG-ACRIN Cancer Research Group Study (E1912) ( Abstract No. LBA-4 )
The partial analysis, with a median follow-up of 33.4 months, was performed on 77 PFS events and 14 deaths. Ibrutinib plus rituximab significantly improved PFS compared to FCR (HR: 0.352; [CI, confidence interval] 95%: 0.223-0.558; P <0.0001); the predetermined limit for PFS has been exceeded. Also the treatment arm with ibrutinib plus rituximab showed an improvement in OS (HR: 0.168; 95% CI: 0.053-0.538; p = 0.0003, predetermined limit for superiority p = 0.0005). 2
In a subgroup of PFS analyzes, ibrutinib plus rituximab showed prolongation of PFS regardless of age, gender, general condition, disease stage or presence / absence of cytogenetic abnormality deletion 11q23. With the current follow-up also ibrutinib plus rituximab was superior to FCR in patients without IgHV mutation (HR: 0.262; CI 95%: 0.137-0.498; p <0.0001), but not in patients with IGHV mutation (HR: 0.435; 95% CI: 0.140-0.1350; p = 0.07). 2
Treatment-related grade 3 or 4 adverse AE events (AEs) were observed in 58% of patients treated with ibrutinib plus rituximab and in 72% of patients treated with FCR (p = 0.0042). The FCR arm was more frequently associated with grade 3 and 4 neutropenia (FCR: 44% compared to ibrutinib plus rituximab: 23%; p <0.0001) and infectious complications (FCR: 17.7% compared to rituximab: 7.1%, p <0.0001). 2
Results from the iLLUMINATED phase 3 study ( abstract No. 691 )
At a median follow-up of 31.3 months, ibrutinib plus obinutuzumab significantly prolonged the PFS assessed by an independent review board (IRC) compared to chlorambucil plus obinutuzumab (median not achieved [NR] vs. 19.0 months; 0.231; 95% CI: 0.145-0.367; P <0.0001), with a 77% reduction in risk of progression or death. 3
Higher PFS values in the armutinib plus obinutuzumab than the chlorambucil plus obinutuzumab arm were also observed in the high-risk population, including cases with IGHV, del11q, del17p and / or TP53 mutation, with 85% reduction in risk progression or death (median NR vs. 14.7 months; HR 0.154; 95% CI: 0.087-0.270; P <0.0001). 5The overall response rate (ORR) assessed by the IRC was also higher for the hybridutinib arm plus obinutuzumab than the chlorambucil plus obinutuzumab arm (88% vs. 73%); also the complete response rates (CR) / complete response with incomplete recovery of the blood count (CRi) were higher, respectively 19% compared to 8%. The minimal residual disease (MRD) was not detectable in the blood and / or bone marrow (<10 -4flow cytometry) in 35% of patients treated with ibrutinib plus obinutuzumab compared to 25% of patients treated with chlorambucil plus obinutuzumab. The 30-month OS rates were 86% for the hybridutinib plus obinutuzumab arm compared to 85% of the most obinutuzumab chlorambucil arm. 3
The most common grade 3 or higher adverse AE (AE) events in the most obinutuzumab-hybridutib arm compared to the most obinutuzumab-chlorambucil arm were: neutropenia (36% vs. 46%), thrombocytopenia (19% vs. 10%), pneumonia (7 % vs. 4%), atrial fibrillation (5% vs. 0%), febrile neutropenia (4% vs. 6%), anemia (4% vs. 8%) and infusion-related reactions (IRR; 2% vs 8%). 5No patients discontinued obinutuzumab due to IRR in the armutinib plus obinutuzumab arm compared to the chlorambucil plus obinutuzumab arm (6%). The EAs led to the interruption of ibrutinib in 16% of patients and led to the interruption of chlorambucil in 9% of patients. The AEs led to the discontinuation of obinutuzumab in the hybridutinib arm plus obinutuzumab (9%) and in the chlorambucil arm plus obinutuzumab (13%). At a follow-up of approximately three years, 70% of patients in the hybridutinib arm plus obinutuzumab continue to be treated with ibrutinib monotherapy. 3
Results from the follow-up up to seven years of the PCYC-1102 phase 1b / 2 study and its extension, PCYC-1103 ( abstract No. 3133 )
The results of these studies showed a lasting efficacy of ibrutinib in newly diagnosed CLL R / R patients. Long-term data showed sustained rates of PFS and OS. The estimated seven-year PFS rates were 80% for newly diagnosed patients and 32% for R / R patients. In particular, the administration of ibrutinib in the first lines of therapy has led to an improvement in PFS for R / R patients. 4
The ORR value was 89% for all patients (CR, 15%), with similar rates in newly diagnosed patients (87% [CR, 32%]) and in CLL R / R patients (89% [ CR, 10%]). Median response duration (DOR) was NR (CI 95%: 0 + -85 +) for newly diagnosed CLL patients and 57 months (CI 95%: 0 + -85 +) for CLL patients R / R. 6 Median PFS was NR (CI 95%: non-evaluable [NE], NE) for newly diagnosed CLL patients and was 51 months (95% CI: 37-70) for CLL R / R patients. 4.6 The median OS was NR for newly diagnosed patients (95% CI: 80-NE) or CLL R / R patients (95% CI: 63-NE), with estimated OS rates at seven years 75% and 52% respectively. 4
Grade 3 or higher adverse events were reported in 74% of newly diagnosed patients and 89% of CLL R / R patients. Among the most common grade 3 or higher adverse events that occurred during treatment were hypertension (new diagnosis, 32%, R / R, 26%), diarrhea (new diagnosis, 16%, R / R, 4%) and hyponatraemia (new diagnosis, 10%, R / R, 0%). Severe hemorrhages of grade 3 or higher atrial fibrillation, thrombocytopenia, anemia and arthralgia have been observed in 11% or less of newly diagnosed and R / R patients. In addition, infections (newly diagnosed, 23%; R / R, 55%) occurred in CLL R / R patients. 6No new or unexpected adverse events were observed, and the frequency 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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Information on the ECOG-ACRIN E1912 study
The phase 3 study (E1912) evaluated previously untreated CLL patients aged up to 70 years, randomized to ibrutinib (420 mg / day until disease progression) and rituximab (50 mg / m 2 on day 1 of cycle 2 325 mg / m 2 on day 2 of cycle 2, 500 mg / m 2 on day 1 of cycles 3-7) (n = 354) or six doses of fludarabine for intravenous (25 mg / m 2 ) and cyclophosphamide (250 mg / m 2 ) days 1-3 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 2day 1 of cycles 2-6) every 28 days (n = 175). The primary endpoint was PFS, with a secondary endpoint of OS. 2
The federally funded study was designed by researchers with ECOG-ACRIN and was conducted through the National Clinical Trials Network of NCI. Pharmacyclics LLC provided hybridutinib under a research and development cooperation agreement with NCI and a separate agreement with ECOG-ACRIN.
Information on the iLLUMINATE study
iLLUMINATE ( PCYC-1130 ) evaluated newly diagnosed CLL patients randomized for continuous administration of hybrid 420 mg once daily until disease progression or unacceptable toxicity, in combination with obinutuzumab 1000 mg intravenously over 6 cycles (n = 113); or chlorambucil on days 1 and 15 of each cycle plus obinutuzumab 1000 mg intravenously over 6 cycles (n = 116). The median age of patients was 71 years and 65% of patients had high-risk genomic characteristics. The primary endpoint was the PFS, assessed by an independent review board. Secondary endpoints included PFS in a high-risk population, undetectable MRD, ORR, OS, and safety. 3
Information on PCYC-1102 and PCYC-1103
With a follow-up of up to a maximum of 7 years, studies ( PCYC-1102 phase 1b / 2 and its extension, PCYC-1103 ) evaluated newly diagnosed CLL R / R patients (n = 132; diagnosis = 31, R / R = 101), including those with high-risk characteristics, who received either ibrutinib 420 mg or 840 mg once daily until disease progression or unacceptable toxicity. At the time of the cutoff, 55% of newly diagnosed patients and 21% of R / R patients continued treatment with ibrutinib, with a median follow-up of 67 months. 4
Information on ibrutinib
Ibrutinib is a first class Bruton tyrosine kinase inhibitor (BTK) that acts by forming a strong covalent bond with BTK to block the transmission of cell survival signals into malignant B cells. 7 By blocking this BTK protein, ibrutinib contributes to the death and reduction of the number of tumor cells, thus slowing the aggravation of the neoplasm. 8
Currently the use of ibrutinib is approved in Europe for the following indications: 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 CLL patients who have already undergone at least one previous therapy .
Mantle cell lymphoma (MCL): adult patients with relapsing or refractory MCL forms.
Waldenström macroglobulinemia (WM): patients who have undergone at least one previous therapy or are being treated with first-line therapy in cases where chemo-immunotherapy is not appropriate.
Ibrutinib is approved in over 90 countries and, to date, has been used to treat more than 135,000 patients worldwide and for all approved indications. 10
The most common adverse reactions observed with ibrutinib include diarrhea, neutropenia, haemorrhage (for example: bruising), musculoskeletal pain, nausea, rash and pyrexia. 9
For a full list of side effects and information on dosage and administration, contraindications and other precautions for the use of ibrutinib, please see the Summary of Product Characteristics (SmPC) .