Zanubrutinib is a potent and highly selective inhibitor of Bruton tyrosine kinase (BTK). In this first-in-human, open-label, multicenter, phase 1 study, patients in part 1 (3 + 3 dose escalation) had ...relapsed/refractory B-cell malignancies and received zanubrutinib 40, 80, 160, or 320 mg once daily or 160 mg twice daily. Part 2 (expansion) consisted of disease-specific cohorts, including treatment-naive or relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). The primary end points were safety and tolerability, and definition of the maximum tolerated dose (part 1). Additional end points included pharmacokinetics/pharmacodynamics and preliminary efficacy. Reported herein are results from 144 patients enrolled in the dose-finding and CLL/SLL cohorts. No dose-limiting toxicities occurred in dose escalation. Median BTK occupancy in peripheral blood mononuclear cells was >95% at all doses. Sustained complete (>95%) BTK occupancy in lymph node biopsy specimens was more frequent with 160 mg twice daily than 320 mg once daily (89% vs 50%; P = .0342). Consequently, 160 mg twice daily was selected for further investigation. With median follow-up of 13.7 months (range, 0.4-30.5 months), 89 CLL/SLL patients (94.7%) remain on study. Most toxicities were grade 1/2; neutropenia was the only grade 3/4 toxicity observed in >2 patients. One patient experienced a grade 3 subcutaneous hemorrhage. Among 78 efficacy-evaluable CLL/SLL patients, the overall response rate was 96.2% (95% confidence interval, 89.2-99.2). Estimated progression-free survival at 12 months was 100%. Zanubrutinib demonstrated encouraging activity in CLL/SLL patients, with a low incidence of major toxicities. This trial was registered at www.clinicaltrials.gov as #NCT02343120.
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•Zanubrutinib is a potent and selective BTK inhibitor with greater selectivity and potentially fewer off-target effects than ibrutinib.•In this study, zanubrutinib was tolerable and demonstrated encouraging activity in relapsed/refractory or treatment-naive CLL patients.
Accurate identification of tumor-derived somatic variants in plasma circulating cell-free DNA (cfDNA) requires understanding of the various biological compartments contributing to the cfDNA pool. We ...sought to define the technical feasibility of a high-intensity sequencing assay of cfDNA and matched white blood cell DNA covering a large genomic region (508 genes; 2 megabases; >60,000× raw depth) in a prospective study of 124 patients with metastatic cancer, with contemporaneous matched tumor tissue biopsies, and 47 controls without cancer. The assay displayed high sensitivity and specificity, allowing for de novo detection of tumor-derived mutations and inference of tumor mutational burden, microsatellite instability, mutational signatures and sources of somatic mutations identified in cfDNA. The vast majority of cfDNA mutations (81.6% in controls and 53.2% in patients with cancer) had features consistent with clonal hematopoiesis. This cfDNA sequencing approach revealed that clonal hematopoiesis constitutes a pervasive biological phenomenon, emphasizing the importance of matched cfDNA-white blood cell sequencing for accurate variant interpretation.
Purpose.
Mutations of the K‐ras gene were identified as a prognostic marker in metastatic colorectal cancer (mCRC). In addition, emerging data suggest that K‐ras mutations are a negative predictor of ...clinical benefit from anti–epidermal growth factor receptor treatment in mCRC. Previously reported data suggest that the longer overall survival (OS) observed with bevacizumab treatment in mCRC is independent of alterations in the Ras/Raf/Mek/Erk pathway. We conducted additional analyses to better describe the clinical benefit of bevacizumab treatment in mCRC relative to K‐ras mutation status.
Patients and Methods.
Additional statistical analyses were done with data from K‐ras mutation analyses in 230 patients who were treated with irinotecan, fluorouracil, and leucovorin (IFL) in combination with either bevacizumab or placebo in a randomized phase III study. Following microdissection, tissue was subject to DNA sequencing to identify K‐ras mutations in codons 12 and 13. Hazard ratios for the bevacizumab group relative to the control group were estimated from an unstratified Cox regression model. The median progression‐free survival (PFS), OS times, and objective response rates were compared.
Results.
K‐ras status was assessed in 230 patients (28.3%). The median PFS was significantly longer in bevacizumab‐treated patients with wild‐type (wt)‐ (13.5 versus 7.4 months; hazard ratio 0.44, p < .0001) and mutant (m)‐K‐ras (9.3 versus 5.5 months; hazard ratio 0.41, p = .0008). A significantly higher response rate for IFL plus bevacizumab was observed only in wt‐K‐ras patients (60.0% versus 37.3%, p = .006) compared with 43.2% versus 41.2% in the m‐K‐ras group.
Conclusion.
Bevacizumab provides significant clinical benefit in patients with mCRC expressing either mutant or wild‐type K‐ras.
This study describes parameters of clinical benefit of bevacizumab treatment in metastatic colorectal cancer patients relative to K‐ras mutation status. Bevacizumab resulted in a statistically significant longer median progression‐free survival time in patients with both wild‐type and mutant K‐ras, suggesting significant clinical benefit regardless of K‐ras status.
Bevacizumab, a monoclonal antibody against vascular endothelial growth factor, increases survival when combined with irinotecan-based chemotherapy in first-line treatment of metastatic colorectal ...cancer (CRC). This randomized, phase II trial compared bevacizumab plus fluorouracil and leucovorin (FU/LV) versus placebo plus FU/LV as first-line therapy in patients considered nonoptimal candidates for first-line irinotecan.
Patients had metastatic CRC and one of the following characteristics: age > or = 65 years, Eastern Cooperative Oncology Group performance status 1 or 2, serum albumin < or = 3.5 g/dL, or prior abdominal/pelvic radiotherapy. Patients were randomly assigned to FU/LV/placebo (n = 105) or FU/LV/bevacizumab (n = 104). The primary end point was overall survival. Secondary end points were progression-free survival, response rate, response duration, and quality of life. Safety was also assessed.
Median survival was 16.6 months for the FU/LV/bevacizumab group and 12.9 months for the FU/LV/placebo group (hazard ratio, 0.79; P = .16). Median progression-free survival was 9.2 months (FU/LV/bevacizumab) and 5.5 months (FU/LV/placebo); hazard ratio was 0.50; P = .0002. Response rates were 26.0% (FU/LV/bevacizumab) and 15.2% (FU/LV/placebo) (P = .055); duration of response was 9.2 months (FU/LV/bevacizumab) and 6.8 months (FU/LV/placebo); hazard ratio was 0.42; P = .088. Grade 3 hypertension was more common with bevacizumab treatment (16% v 3%) but was controlled with oral medication and did not cause study drug discontinuation.
Addition of bevacizumab to FU/LV as first-line therapy in CRC patients who were not considered optimal candidates for first-line irinotecan treatment provided clinically significant patient benefit, including statistically significant improvement in progression-free survival.
In a phase III trial, combining bevacizumab (BV)--a recombinant, humanized, monoclonal antibody targeting vascular endothelial growth factor--with irinotecan, bolus fluorouracil (FU), and leucovorin ...(LV; IFL) increased survival compared with IFL alone in first-line treatment of patients with metastatic colorectal cancer (CRC). Results for the parent study of IFL/BV versus IFL/placebo are reported elsewhere. Here, we describe efficacy and safety results for the third patient cohort in this trial, who received BV combined with FU/LV, and compare them with results for concurrently enrolled patients who received IFL.
Patients (N = 923) were randomly assigned to receive IFL/placebo (control), IFL/BV, or FU/LV/BV. Bevacizumab (Avastin; Genentech Inc, South San Francisco, CA) 5 mg/kg was administered intravenously every 2 weeks. Before an interim analysis confirmed acceptable safety for IFL/BV, 313 patients were concurrently randomly assigned to these three arms; after this analysis, the FU/LV/BV arm was discontinued.
Median overall survivals were 18.3 and 15.1 months with FU/LV/BV (n = 110) and IFL/placebo (n = 100), respectively. Median progression-free survivals were 8.8 and 6.8 months, respectively. Overall response rates were 40.0% and 37.0%, and median response durations were 8.5 and 7.2 months, respectively. Adverse events consistent with those expected from FU/leucovorin- or IFL-based regimens were seen, as were modest increases in hypertension and bleeding in the bevacizumab arm, which were generally easily managed.
The FU/LV/BV regimen seems as effective as IFL and has an acceptable safety profile. FU/LV/BV is an active alternative treatment regimen for patients with previously untreated metastatic CRC.
To investigate the efficacy and safety of bevacizumab plus carboplatin and paclitaxel in patients with advanced or recurrent non-small-cell lung cancer.
In a phase II trial, 99 patients were randomly ...assigned to bevacizumab 7.5 (n = 32) or 15 mg/kg (n = 35) plus carboplatin (area under the curve = 6) and paclitaxel (200 mg/m(2)) every 3 weeks or carboplatin and paclitaxel alone (n = 32). Primary efficacy end points were time to disease progression and best confirmed response rate. On disease progression, patients in the control arm had the option to receive single-agent bevacizumab 15 mg/kg every 3 weeks.
Compared with the control arm, treatment with carboplatin and paclitaxel plus bevacizumab (15 mg/kg) resulted in a higher response rate (31.5% v 18.8%), longer median time to progression (7.4 v 4.2 months) and a modest increase in survival (17.7 v 14.9 months). Of the 19 control patients that crossed over to single-agent bevacizumab, five experienced stable disease, and 1-year survival was 47%. Bleeding was the most prominent adverse event and was manifested in two distinct clinical patterns; minor mucocutaneous hemorrhage and major hemoptysis. Major hemoptysis was associated with squamous cell histology, tumor necrosis and cavitation, and disease location close to major blood vessels.
Bevacizumab in combination with carboplatin and paclitaxel improved overall response and time to progression in patients with advanced or recurrent non-small-cell lung cancer. Patients with nonsquamous cell histology appear to be a subpopulation with improved outcome and acceptable safety risks.
This phase II trial investigated the safety and efficacy of two doses of bevacizumab, a monoclonal antibody to vascular endothelial growth factor, plus fluorouracil (FU)/leucovorin (LV) versus FU/LV ...alone in patients with metastatic colorectal cancer.
One hundred four previously untreated patients with measurable metastatic colorectal cancer were randomly assigned to one of the following three treatment groups: 36 to FU (500 mg/m(2))/LV (500 mg/m(2)) alone, 35 to FU/LV + low-dose bevacizumab (5 mg/kg every 2 weeks), and 33 to FU/LV + high-dose bevacizumab (10 mg/kg every 2 weeks). FU/LV was given weekly for the first 6 weeks of each 8-week cycle.
Compared with the FU/LV control arm, treatment with bevacizumab (at both dose levels) plus FU/LV resulted in higher response rates (control arm, 17%, 95% confidence interval CI, 7% to 34%; low-dose arm, 40%, 95% CI, 24% to 58%; high-dose arm, 24%, 95% CI, 12% to 43%), longer median time to disease progression (control arm, 5.2 months, 95% CI, 3.5 to 5.6 months; low-dose arm, 9.0 months, 95% CI, 5.8 to 10.9 months; high-dose arm, 7.2 months, 95% CI, 3.8 to 9.2 months), and longer median survival (control arm, 13.8 months; 95% CI, 9.1 to 23.0 months; low-dose arm, 21.5 months, 95% CI, 17.3 to undetermined; high-dose arm, 16.1 months; 95% CI, 11.0 to 20.7 months). After cross-over, two of 22 patients had a partial response to bevacizumab alone. Thrombosis was the most significant adverse event and was fatal in one patient. Hypertension, proteinuria, and epistaxis were other potential safety concerns.
The encouraging results of this randomized trial support further study of bevacizumab 5 mg/kg plus chemotherapy as first-line therapy for metastatic colorectal cancer.
Bruton tyrosine kinase (BTK) inhibitors have demonstrated a high degree of efficacy in the treatment of B cell malignancies characterized by constitutive B cell receptor activation, including chronic ...lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).
The efficacy and safety of zanubrutinib, an investigational highly selective BTK inhibitor, was evaluated in this single-arm, phase 2 study of Chinese patients with relapsed/refractory CLL/SLL. The primary endpoint was overall response rate as assessed by an independent review committee.
Of the 91 evaluable patients, 77 (84.6%) achieved a response, with three (3.3%), 54 (59.3%), and 20 (22%) patients achieving a complete response, partial response, and partial response with lymphocytosis, respectively, after a median follow-up of 15.1 months. The estimated 12-month event-free rate for duration of response was 92.9%. The most commonly reported grade ≥ 3 adverse events (AEs) were neutropenia (44%), thrombocytopenia (15.4%), lung infection/pneumonia (13.2%), upper respiratory tract infection (9.9%), and anemia (8.8%). The 12-month overall survival rate was 96%. Eight (9.0%) patients discontinued zanubrutinib due to AEs, and seven (8.0%) patients required at least one dose reduction.
Treatment of patients with relapsed/refractory CLL/SLL with zanubrutinib was generally well tolerated and resulted in a high overall response rate, thereby conferring a favorable benefit-risk profile.
Prospectively registered in China public registry (CTR20160890) on December 7, 2016: http://www.chinadrugtrials.org.cn/. Retrospectively registered in ClinicalTrials.gov (NCT03206918) on July 2, 2017.
The existence of factors that stimulate blood vessel growth, thereby recruiting a neovascular supply to nourish a growing tumour, was postulated many decades ago, although the identification and ...isolation of these factors proved elusive. Now, vascular endothelial growth factor (VEGF), which was identified in the 1980s, is recognized as an essential regulator of normal and abnormal blood vessel growth. In 1993, it was shown that a monoclonal antibody that targeted VEGF results in a dramatic suppression of tumour growth in vivo, which led to the development of bevacizumab (Avastin; Genentech), a humanized variant of this anti-VEGF antibody, as an anticancer agent. The recent approval of bevacizumab by the US FDA as a first-line therapy for metastatic colorectal cancer validates the ideas that VEGF is a key mediator of tumour angiogenesis and that blocking angiogenesis is an effective strategy to treat human cancer.
Apoptosis ligand 2/tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL)-a member of the tumor necrosis factor cytokine family-induces apoptosis by activating the extrinsic pathway ...through the proapoptotic death receptors DR4 and DR5. Recombinant human Apo2L/TRAIL (rhApo2L/TRAIL) has broad potential as a cancer therapy. To the best of our knowledge, this is the first in-human clinical trial to assess the safety, tolerability, pharmacokinetics, and antitumor activity of multiple intravenous doses of rhApo2L/TRAIL in patients with advanced cancer.
This phase I, open-label, dose-escalation study treated patients with advanced cancer with rhApo2L/TRAIL doses ranging from 0.5 to 30 mg/kg/d, with parallel dose escalation for patients without liver metastases and with normal liver function (cohort 1) and for patients with liver metastases and normal or mildly abnormal liver function (cohort 2). Doses were given daily for 5 days, with cycles repeating every 3 weeks. Assessments included adverse events (AEs), laboratory tests, pharmacokinetics, and imaging to evaluate antitumor activity.
Seventy-one patients received a mean of 18.3 doses; seven patients completed all eight treatment cycles. The AE profile of rhApo2L/TRAIL was similar in cohorts 1 and 2. The most common AEs were fatigue (38%), nausea (28%), vomiting (23%), fever (23%), anemia (18%), and constipation (18%). Liver enzyme elevations were concurrent with progressive metastatic liver disease. Two patients with sarcoma (synovial and undifferentiated) experienced serious AEs associated with rapid tumor necrosis. Two patients with chondrosarcoma experienced durable partial responses to rhApo2L/TRAIL.
At the tested schedule and dose range, rhApo2L/TRAIL was safe and well tolerated. Dose escalation achieved peak rhApo2L/TRAIL serum concentrations equivalent to those associated with preclinical antitumor efficacy.
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