Efficacy Of Ibrutinib In Patients Research Articles

Ibrutinib in c-MYC and HER2 Amplified Oesophagogastric Carcinoma: Results of the Proof-of-Concept iMYC Study.

Oesophagogastric (OG) cancer is a highly lethal disease requiring novel treatment options. c-MYC and/or HER-2 amplified oesophageal cancer models have demonstrated sensitivity to BTK inhibition with ibrutinib. We evaluated the safety and efficacy of ibrutinib in patients with c-MYC and/or HER2 amplified pre-treated advanced OG cancer. c-MYC and HER2 amplification status were determined by FISH. The primary endpoint was overall response rate (ORR). Secondary endpoints were disease control rate (DC) at 8 weeks, safety, progression-free survival (PFS) and overall survival (OS). Eleven patients were enrolled. Eight patients had c-MYC amplified tumours, six were HER2 amplified and three were c-MYC and HER2 co-amplified. Grade ≥ 3 adverse events were fever, neutropenia, and vomiting. Grade ≥ 3 gastrointestinal haemorrhage occurred in three patients and was fatal in two cases. Among seven evaluable patients, three patients (43%) achieved a best response of SD at 8 weeks. No PR or CR was observed. Disease control was achieved for 32 weeks in one patient with a dual c-MYC and HER2 highly co-amplified tumour. The median PFS and OS were 1.5 (95% CI: 0.8–5.1) and 5.1 (95% CI: 0.8–14.5) months, respectively. Ibrutinib had limited clinical efficacy in patients with c-MYC and/or HER2 amplified OG cancer. Unexpected gastrointestinal bleeding was observed in 3 out of 8 treated patients which was considered a new safety finding for ibrutinib in this population.

Durable ibrutinib responses in relapsed/refractory marginal zone lymphoma: long-term follow-up and biomarker analysis

AbstractAdvanced marginal zone lymphoma (MZL) is an incurable B-cell malignancy dependent on B-cell receptor signaling. The phase 2 PCYC-1121 study demonstrated the safety and efficacy of single-agent ibrutinib 560 mg/d in 63 patients with relapsed/refractory MZL treated with prior rituximab (RTX) or rituximab-based chemoimmunotherapy (RTX-CIT). We report the final analysis of PCYC-1121 with median follow-up of 33.1 months (range: 1.4-44.6). Overall response rate (ORR) was 58%; median duration of response (DOR) was 27.6 months (95% confidence interval [CI]: 12.1 to not estimable [NE]); median progression-free survival (PFS) was 15.7 months (95% CI: 12.2-30.4); and median overall survival (OS) was not reached (95% CI: NE to NE). Patients with prior RTX treatment had better outcomes (ORR: 81%; median DOR: not reached [95% CI: 12.2 to NE]; median PFS: 30.4 months [95% CI: 22.1 to NE]; median OS: not reached [95% CI: 30.3 to NE]) vs those with prior RTX-CIT treatment (ORR: 51%; DOR: 12.4 months [95% CI: 2.8 to NE]; PFS: 13.8 months [95% CI: 8.3-22.5]; OS: not reached [95% CI: NE to NE]). ORRs were 63%, 47%, and 62% for extranodal, nodal, and splenic subtypes, respectively. With up to 45 months of ibrutinib treatment, the safety profile remained consistent with prior reports. The most common grade ≥3 event was anemia (16%). Exploratory biomarker analysis showed NF-κB pathway gene mutations correlated with outcomes. Final analysis of PCYC-1121 demonstrated long-term safety and efficacy of ibrutinib in patients with relapsed/refractory MZL, regardless of prior treatment or MZL subtype. This trial was registered at www.clinicaltrials.gov as #NCT01980628.

Ibrutinib for the Treatment of Bing-Neel Syndrome

Ibrutinib for the Treatment of Bing-Neel Syndrome

Ibrutinib for chronic graft-versus-host disease after failure of prior therapy

AbstractChronic graft-versus-host disease (cGVHD) is a serious complication of allogeneic stem cell transplantation with few effective options available after failure of corticosteroids. B and T cells play a role in the pathophysiology of cGVHD. Ibrutinib inhibits Bruton tyrosine kinase in B cells and interleukin-2–inducible T-cell kinase in T cells. In preclinical models, ibrutinib reduced severity of cGVHD. This multicenter, open-label study evaluated the safety and efficacy of ibrutinib in patients with active cGVHD with inadequate response to corticosteroid-containing therapies. Forty-two patients who had failed 1 to 3 prior treatments received ibrutinib (420 mg) daily until cGVHD progression. The primary efficacy end point was cGVHD response based on 2005 National Institutes of Health criteria. At a median follow-up of 13.9 months, best overall response was 67%; 71% of responders showed a sustained response for ≥20 weeks. Responses were observed across involved organs evaluated. Most patients with multiple cGVHD organ involvement had a multiorgan response. Median corticosteroid dose in responders decreased from 0.29 mg/kg per day at baseline to 0.12 mg/kg per day at week 49; 5 responders discontinued corticosteroids. The most common adverse events were fatigue, diarrhea, muscle spasms, nausea, and bruising. Plasma levels of soluble factors associated with inflammation, fibrosis, and cGVHD significantly decreased over time with ibrutinib. Ibrutinib resulted in clinically meaningful responses with acceptable safety in patients with ≥1 prior treatments for cGVHD. Based on these results, ibrutinib was approved in the United States for treatment of adult patients with cGVHD after failure of 1 or more lines of systemic therapy. This trial was registered at www.clinicaltrials.gov as #NCT02195869.

Mapping genetic vulnerabilities reveals BTK as a novel therapeutic target in oesophageal cancer

ObjectiveOesophageal cancer is the seventh most common cause of cancer-related death worldwide. Disease relapse is frequent and treatment options are limited.DesignTo identify new biomarker-defined therapeutic approaches for patients with oesophageal...

Ibrutinib exerts potent antifibrotic and antitumor activities in mouse models of pancreatic adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense stromal fibroinflammatory reaction that is a major obstacle to effective therapy. The desmoplastic stroma comprises many inflammatory cells, in particular mast cells as key components of the PDAC microenvironment, and such infiltration correlates with poor patient outcome. Indeed, it has been hypothesized that stromal ablation is critical to improve clinical response in patients with PDAC. Ibrutinib is a clinically approved Bruton's tyrosine kinase inhibitor that inhibits mast cells and tumor progression in a mouse model of β-cell tumorigenesis. Here, we show that ibrutinib is highly effective at limiting the growth of PDAC in both transgenic mouse and patient-derived xenograft models of the disease. In these various experimental settings, ibrutinib effectively diminished fibrosis, extended survival, and improved the response to clinical standard-of-care therapy. Our results offer a preclinical rationale to immediately evaluate the clinical efficacy of ibrutinib in patients with PDAC.

Safety and Efficacy of Ibrutinib in Patients with Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL) Who Have Undergone Prior Allogeneic Stem Cell Transplant

Safety and Efficacy of Ibrutinib in Patients with Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL) Who Have Undergone Prior Allogeneic Stem Cell Transplant

Safety and Efficacy of Ibrutinib in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Who Have Undergone Prior Allogeneic Stem Cell Transplant

Introduction: Ibrutinib (Imbruvica®), a first-in-class Bruton’s tyrosine kinase inhibitor is a once-daily single-agent approved by the US FDA for patients with chronic lymphocytic leukemia (CLL) who have received ≥1 prior therapy, and for CLL with a 17p deletion. The phase III trial evaluating the efficacy and safety of ibrutinib in patients with relapsed/refractory CLL or small lymphocytic leukemia has previously been reported (Byrd et al. N Engl J Med, 2014). Allogeneic hematopoietic stem cell transplantation (HSCT) is also used to treat CLL, particularly in those who are at high risk. Patients with CLL who relapse after allogeneic HSCT are extremely difficult to treat with chemotherapy due to impaired hematopoietic reserve and/or infections. Furthermore, both B and T cells are known to play a role in the immunopathophysiology of graft-versus-host disease (GVHD), and in preclinical studies, ibrutinib, which inhibits both ITK and BTK, reversed established chronic GVHD. To evaluate whether ibrutinib is safe and effective in treating patients with CLL with a history of prior allogeneic HSCT, we evaluated the subset of patients enrolled in ibrutinib clinical trials who had undergone prior HSCT.Methods: Data were collected for patients with relapsed/refractory CLL who had undergone allogeneic HSCT and had been treated with ibrutinib, either as a single agent or in combination with ofatumumab, in 1 of 4 clinical trials (PCYC-1102, PCYC-1109, PCYC-1112, and PCYC-1117). Two of the studies (PCYC-1112 and PCYC-1117) allowed only patients who were >6 months post-HSCT and without GVHD to enroll. Efficacy evaluations included assessment of overall response rate (ORR) by iwCLL criteria, duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Safety evaluations included reporting of adverse events (AEs), including serious AEs (SAEs).Results: A total of 16 patients from 4 ibrutinib clinical trials had undergone prior allogeneic HSCT. Median patient age was 54.5 years (range, 43-68); 12.5% were ≥ 65 years of age, 11 were male, and all 16 patients had an ECOG performance status of 0 or 1. Chromosomal abnormalities del17p and del11q were reported in 10 and 3 patients, respectively. More than 4 prior therapies were reported for 12 patients. Of the 16 patients, 13 had received an intervening salvage therapy between allogeneic HSCT and the start of ibrutinib treatment. The median time since the most recent transplant was 27 months (range, 8-115). Baseline neutropenia, anemia, and thrombocytopenia were reported in 31%, 25%, and 38%, respectively. Median time on ibrutinib was 18.1 months (range, 0.4-38.8) including 12 patients who were treated with ibrutinib for >12 months. At the time of data cut-off, 11 patients were continuing treatment. Reasons for discontinuation included disease progression (n=2), AEs (n=2), and withdrawal of consent (n=1). No dose reductions were reported. Investigator-assessed responses included 2 complete responses, 9 partial responses, and 3 partial responses with lymphocytosis, resulting in a best ORR of 87.5%. Median DOR, median PFS, and median OS were not reached at a median follow-up of 23 months. The 24-month PFS and OS rates were each 77% and 75%, respectively. Treatment-emergent grade ≥3 SAEs were observed in 11 patients and included infections (n=6), with the remaining events occurring in 1 patient each, including febrile neutropenia, atrial flutter, colitis, perirenal hematoma, subdural hematoma, postprocedural hemorrhage, hypercalcemia, bone lesion, syncope, hematuria, urinary retention, and dyspnea. The only AE leading to discontinuation of ibrutinib was pneumonia in 2 patients; both were fatal events (at 0.9 and 2.3 months). Two additional deaths occurred on study due to disease progression at 24 and 28 months.Conclusion: Ibrutinib was well tolerated in patients who had undergone prior allogeneic HSCT, with a safety profile similar to that observed in the overall population of patients with relapsed/refractory CLL. The best ORR of 87.5% in this subgroup was also consistent with the 90% reported for the broader relapsed/refractory population in the PCYC-1102 study of single-agent ibrutinib. These data support use of ibrutinib in CLL patients with previous allogeneic HSCT and exploration of ibrutinib treatment for chronic GVHD (ongoing clinical trial: clinicaltrials.gov NCT 02195869). DisclosuresCoutre:Janssen, Pharmacyclics: Honoraria, Research Funding. O’Brien:Amgen, Celgene, GSK: Consultancy; CLL Global Research Foundation: Membership on an entity’s Board of Directors or advisory committees; Emergent, Genentech, Gilead, Infinity, Pharmacyclics, Spectrum: Consultancy, Research Funding; MorphoSys, Acerta, TG Therapeutics: Research Funding. Byrd:Pharmacyclics: Research Funding. Hillmen:Pharmacyclics, Janssen, Gilead, Roche: Honoraria, Research Funding. Brown:Sanofi, Onyx, Vertex, Novartis, Boehringer, GSK, Roche/Genentech, Emergent, Morphosys, Celgene, Janssen, Pharmacyclics, Gilead: Consultancy. Mato:Pharamcyclics, Genentech, Celegene, Millennium : Speakers Bureau. Miklos:Pharmacyclics: Research Funding. Zhou:Pharmacyclics: Employment. Fardis:Pharmacyclics: Employment. Styles:Pharmacyclics: Employment. Jaglowski:Pharmacyclics: Research Funding.