On December 10, 2018 Janssen pharmaceutical companies at Johnson & Johnson reported new results from three key studies of IMBRUVICA (ibrutinib) in chronic lymphocytic leukemia (CLL), a form of difficult blood cancer treat and the most common form of leukemia in adults (Press release, Johnson & Johnson, DEC 10, 2018, View Source [SID1234531991]). 1 The findings were presented at the 60th to annual meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) held in San Diego (California).
Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:
Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing
Schedule Your 30 min Free Demo!
The results of the phase 3 study sponsored by the National Cancer Institute (NCI) (E1912), led by the ECOG-ACRIN cancer research group, were presented during the last oral summary session. The study evaluated the combination of ibrutinib plus rituximab compared to a regimen for chemotherapy of fludarabine, cyclophosphamide, and rituximab (FCR) in patients 70 years of age or younger with CLL who had not received prior treatment. After almost three years of follow-up, the data showed that ibrutinib plus rituximab significantly prolonged progression-free survival (PFS) and overall survival (OS) compared to the FCR combination. two
The iLLUMINATE (PCYC-1130) Phase 3 data was also presented in an oral session and simultaneously published in The Lancet Oncology . The results showed that the combination of ibrutinib plus obinutuzumab significantly improved progression-free survival versus the combination of chlorambucil and obinutuzumab in patients with newly diagnosed CLL. 3 These data recently supported the submission of a Type II variation request to the European Medicines Agency (EMA), which seeks approval to expand the use of ibrutinib in combination with obinutuzumab in adults with CLL who have not received prior treatment.
In addition, the ibrutinib data from the phase 1b / 2 study and its extension study (PCYC-1102, PCYC-1103), with up to seven years of follow-up in patients with newly diagnosed CLL and relapsed / recurrent (R / R) , showed long-term survival benefits as monotherapy, which implies the longer follow-up of a Bruton tyrosine kinase inhibitor (BTK) in CLL. 4
"The results of the iLLUMINATE and ECOG-ACRIN studies show an impressive survival without prolonged progression for the relevant combinations based on ibrutinib, compared to the regimens of chemoimmunotherapy usually used," said Dr. Carol Moreno, a hematologist at the Hospital de la Santa Creu i Sant Pau, Autonomous University of Barcelona (Spain). "These non-chemotherapeutic regimens represent an advance in the way we might consider treating patients, including the youngest and those with high risk characteristics in CLL, with potential to address the compromise between efficacy and toxicity for patients. »
"The data presented in the ASH (Free ASH Whitepaper) provide more convincing evidence of the clinical benefit that ibrutinib can offer to patients across the spectrum of CLL treatment. The long-term data also offer reliability in terms of sustained activity for patients, "explained Dr. Catherine Taylor, head of the area of hematology therapy in Europe, Middle East and Africa (EMEA) of Janssen-CilagLimited. "We continue to explore the full potential of ibrutinib through a comprehensive clinical development program, in order to improve the results and change what the diagnosis of blood cancer means for patients."
JanssenBiotech, Inc. and PharmacyclicsLLC, an AbbVie company, jointly develop and market ibrutinib, a first-class BTK inhibitor.
Results of the randomized phase 3 study of ibrutinib treatment (PCI-32765) versus chemoimmunotherapy with CRF in younger patients with CLL who were not previously treated: a study by the ECOG-ACRIN cancer research group (E1912) ( summary No. LBA-4 )
With an average follow-up of 33.4 months, the provisional analysis observed 77 cases of progression-free survival and 14 deaths. The combination of ibrutinib plus rituximab significantly improved progression-free survival compared to the FCR combination (hazard ratio: 0.352, 95% confidence interval [CI]: 0.223-0.558, p <0.0001); the pre-established limit for survival without progression was crossed. The treatment group of ibrutinib plus rituximab also showed an improvement in overall survival (hazard ratio: 0.168, 95% CI: 0.053-0.538, p = 0.0003, pre-established upper limit p = 0.0005). two
In a progression-free survival subgroup analysis, the combination ibrutinib plus rituximab showed a prolonged progression-free survival independent of age, sex, functional status, disease phase or the presence / absence of cytogenetic abnormalities, 11q23 deletion. With the current follow-up, the ibrutinib plus rituximab combination was also superior to the FCR combination in patients who did not have mutations in IGHV (risk ratio: 0.262, 95% CI: 0.137-0.498, p <0.0001) but not in patients who presented mutations in IGHV (hazard ratio: 0.435, 95% CI: 0.140-0.1350, p = 0.07). two
Adverse reactions associated with grade 3/4 treatment were observed in 58% of patients treated with the combination ibrutinib plus rituximab, and in 72% of patients treated with HRG (p = 0.0042). The FCR combination was more frequently associated with grade 3 and 4 neutropenia (FCR: 44% versus the combination ibrutinib plus rituximab: 23%, p <0.0001) and infectious complications (FCR: 17.7% vs. the combination ibrutinib plus rituximab: 7.1%, p <0.0001). two
Results of the 3 phase iLLUMINATE study ( summary # 691 )
At an average follow-up of 31.3 months, the combination of ibrutinib plus obinutuzumab significantly prolonged progression-free survival as assessed by the Independent Review Committee (ICR), compared with the combination of chlorambucil and obinutuzumab (average not reached versus 19, 0 months, risk ratio 0.231, 95% CI: 0.145-0.367, p <0.0001), with a 77% reduction in the risk of progression or death. 3
High progression survival was also observed in the ibrutinib plus obinutuzumab combination group compared to the combination of chlorambucil plus obinutuzumab, even in those patients who had mutations in IGHV, del11q, del17p and / or TP53, with an 85% reduction in the risk of progression or death (average not reached versus 14.7 months, risk ratio 0.154, 95% CI: 0.087-0.270, p <0.0001). 5 In addition, the overall response rate (ORR) assessed by the IRC was higher in the ibrutinib plus obinutuzumab group compared to the chlorambucil plus obinutuzumab group (88% versus 73%); Complete response (CR) / complete response with incomplete blood recovery (CRi) rates were also higher, with 19% versus 8%, respectively. No minimal residual disease (MRE) was detected in the blood and / or spinal cord (<10 -4by flow cytometry) in 35% of patients treated with ibrutinib plus obinutuzumab, compared to 25% of patients treated with chlorambucil plus obinutuzumab. Overall survival rates at 30 months were 86% for the ibrutinib plus obinutuzumab group, versus 85% for the chlorambucil plus obinutuzumab group. 3
The most common adverse events of grade 3 or higher in the ibrutinib plus obinutuzumab group versus the chlorambucil plus obinutuzumab group 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 perfusion-related reactions (IRR, 2% vs 8%). %). 5No patient discontinued treatment with obinutuzumab due to infusion-related reactions in the ibrutinib plus obinutuzumab combination group, compared with the chlorambucil plus obinutuzumab group (6%). Adverse reactions continue to cause the interruption of ibrutinib treatment in 16% of patients and involves the interruption of chlorambucil intake in 9% of patients. Adverse reactions caused the interruption of treatment with obinutuzumab in the group of ibrutinib plus obinutuzumab (9%) and in the group of chlorambucil plus obinutuzumab (13%). With an approximate follow-up of three years, 70% of the patients in the ibrutinib plus obinutuzumab group continued on monotherapy with ibrutinib.3
Results of up to seven years of follow-up in the PCYC-1102 phase 1b / 2 study and its extension, PCYC-1103 ( abstract number 3133 )
The results of these studies demonstrated a lasting efficacy of ibrutinib in patients with recently diagnosed or relapsing / recurrent CLL. These long-term data showed sustained overall progression-free survival and response rates. The estimated 7-year progression-free survival rates were 80% for patients with newly diagnosed disease, and 32% for patients with recurrent / relapsing disease. In particular, the administration of ibrutinib in earlier lines of therapy resulted in improved progression-free survival outcomes in relapsed / recurrent patients. 4
The overall response rate was 89% for all patients (complete response, 15%) with similar rates in patients with recently diagnosed CLL (87% [complete response, 32%] and relapsed / recurrent (89% [response complete, 10%]) The average response duration (DOR) (95% CI: 0 + -85 +) was not reached in the newly diagnosed CLL patients and was 57 months (95% CI: 0+ . -85+) for CLL patients relapsed / recurrent 6 survival was not reached average progression (95% IC: not estimable [NE], NE) for CLL patients newly diagnosed was 51 months (95% CI: 37-70) for relapsed / recurrent CLL patients 4.6 The average general response was not reached in patients with recently diagnosed CLL (95% CI: 80-NE) or relapsed / recurrent (95% CI: 63-NE), with estimated overall response rates at seven years of 75% and 52%, respectively. 4
Grade 3 or higher adverse reactions were recorded in 74% of patients with recently diagnosed CLL and in 89% of relapsed / recurrent patients. Among the most common adverse reactions of grade 3 or higher that arose with treatment are hypertension (recent diagnosis, 32%, relapse / recurrent, 26%), diarrhea (recent diagnosis, 16%, relapse / recurrent, 4%) and hyponatremia (recent diagnosis, 10%; relapse / recurrent, 0%). In 11% or less of newly diagnosed or relapsed / recurrent patients, significant bleeding and grade 3 or higher articular fibrillation, thrombocytopenia, anemia, and arthralgia were detected. In addition, infections (recent diagnosis, 23%; relapse / recurrent,6 No new or unexpected adverse reactions were observed and the prevalence of most of the adverse reactions of grade 3 or higher and severe decreased with time, except hypertension. 6
#FINISH#
About the ECOG-ACRIN E1912 study
The phase 3 study (E1912) evaluated patients with CLL aged 70 years or younger who had not received previous treatment and who had been randomly assigned to receive 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 stages of fludarabine 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 2on day 1 of cycles 2-6) every 28 days (n = 175). The primary endpoint was survival without progression with a secondary criterion of overall survival. two
The study, financed with federal funds from the US UU., Was designed by researchers together with ECOG-ACRIN. It was conducted in the NCI national clinical trials network. PharmacyclicsLLC provided ibrutinib under a research and development cooperation agreement with the NCI and an independent agreement with ECOG-ACRIN.
About the iLLUMINATE study
iLLUMINATE ( PCYC-1130) evaluated newly diagnosed patients with CLL who were randomized to receive ibrutinib 420 mg once a day continuously until disease progression or unacceptable toxicity in combination with obinutuzumab 1000 mg intravenously 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 average age of the patients was 71 years and 65% of the patients presented high-risk genomic characteristics. The primary endpoint was survival without progression, assessed by an Independent Review Committee.3
About PCYC-1102 and PCYC-1103
With a follow-up of up to seven years, the studies (phase 1b / 2, PCYC-1102 and its extension, PCYC-1103 ) evaluated patients with newly diagnosed CLL and relapsed / recurrent (n = 132; newly diagnosed = 31; relapse / recurrent = 101), including those with high-risk characteristics, who received 420 mg or 840 mg once daily of ibrutinib until disease progression or unacceptable toxicity. At the deadline, 55% of newly diagnosed patients and 21% of relapsed / recurrent patients continued to take ibrutinib, with an average follow-up of 67 months. 4
About ibrutinib
Ibrutinib is a first-class inhibitor of Bruton’s tyrosine kinase (BTK), which works by forming a strong covalent bond with BTK to block the transmission of cellular survival signals within malignant B cells. 7 By blocking this BTK protein, ibrutinib helps eliminate and reduce the number of cancer cells, thereby delaying the progression of cancer. 8
Currently, ibrutinib is authorized in Europe for the following uses: 9
chronic lymphocytic leukemia (CLL): As a single agent for the treatment of adult patients with CLL who have not undergone previous treatment, and as a single agent or in combination with bendamustine and rituximab (BR) for the treatment of adult patients with CLL who have received less a previous treatment.
Mantle cell lymphoma (MCL): Adult patients with relapsed / recurrent MCL.
Waldenström macroglobulinemia (MW): Adult patients who have received at least one previous treatment or first-line treatment for patients not suitable for chemoimmunotherapy.
Ibrutinib is approved in more than 90 countries and, to date, it has been used to treat more than 135,000 patients worldwide for its approved indications. 10
The most common adverse reactions observed with ibrutinib are diarrhea, neutropenia, haemorrhage (eg, bruising), musculoskeletal pain, nausea, rash, and pyrexia. 9
Consult the summary of product characteristics for a complete list of side effects and information on dosing and administration, contraindications and other precautions when taking ibrutinib.