In the Literature – April 2017
In This Article
- Venetoclax plus Rituximab Improves Outcomes in Chronic Lymphocytic Leukemia
- Lay Navigation Reduces Medicare Costs, Resource Utilization
- Adding Antiandrogen Therapy Improves Survival in Recurrent Prostate Cancer
Venetoclax plus Rituximab Improves Outcomes in Chronic Lymphocytic Leukemia
In preclinical models of B-cell malignancy, researchers observed synergy when the BCL2 inhibitor venetoclax (Venclexta) was combined with the anti-CD20 monoclonal antibody rituximab (Rituxan). This led researchers to conduct a phase 1b dose-escalation study that assessed the safety, pharmacokinetics, and activity of venetoclax in combination with rituximab in patients with relapsed or refractory chronic lymphocytic leukemia (CLL), the results of which were recently published in Lancet Oncology (Seymour JF, et al. Lancet Oncol. 2017;18:230-240).
The phase 1b dose-escalation study included 49 patients with relapsed or refractory CLL or small lymphocytic lymphoma. The patients received daily doses of venetoclax that were escalated to a target dose of 200 mg to 600 mg, followed by monthly rituximab at 375 mg/m2 in month 1 and 500 mg/m2 in months 2 to 6. Researchers permitted drug cessation for patients with a complete response (including complete response with incomplete marrow recovery) or negative bone marrow minimal residual disease. At the time of analysis, patients were still receiving treatment, with ongoing follow-up.
The primary end points were to assess the safety profile of the combination to determine the maximum tolerated dose, and to establish the recommended phase 2 dose of venetoclax when combined with rituximab. The secondary end points included overall response rate (ORR), duration of response, and time to tumor progression.
Of the 49 patients who received the combination treatment, 42 (86%) achieved ORR, including a complete response in 25 (51%) patients, and 28 (57%) patients attained negative marrow minimal residual disease. The 2-year estimates of progression-free survival and ongoing response were 82% and 89%, respectively.
Overall, 13 patients who responded to venetoclax plus rituximab stopped therapy; 11 of these patients had minimal residual disease–negative response and did not have disease progression after stopping therapy, whereas 2 patients with a minimal residual disease–positive complete response had disease progression after 24 months of stopping therapy, with response regained after restarting venetoclax and remaining on therapy.
Common grade 1 or 2 adverse events included upper respiratory tract infections (57%), diarrhea (55%), and nausea (51%). Grade 3 or 4 adverse events were reported in 37 patients, with the most common being neutropenia (53%), thrombocytopenia (16%), anemia (14%), febrile neutropenia (12%), and leukopenia (12%). The most common serious adverse events were pyrexia (12%), febrile neutropenia (10%), lower respiratory tract infection (6%), and pneumonia (6%). A maximum dose was not identified, and the recommended venetoclax dose for the phase 2 study is 400 mg in combination with rituximab.
“These results demonstrate that venetoclax and rituximab can be safely delivered without compromise of venetoclax dose, offering a treatment strategy that yields high rates of deep responses that can be maintained for substantial time periods when patients cease therapy,” the researchers concluded.
Lay Navigation Reduces Medicare Costs, Resource Utilization
Previous research has shown that navigation programs can improve access to care, enhance coordination of care, and address barriers to achieving timely, high-quality healthcare. However, limited data exist on the economic impact of implementing a lay navigation program. A recent study evaluated the influence of lay navigation on healthcare spending and resource use in Medicare patients with cancer who used the Patient Care Connect Program (PCCP) that was implemented within the University of Alabama at Birmingham Health System Cancer Community Network (CCN). The goal of the PCCP model was to meet the Triple Aim of improved healthcare, better health, and lower costs by integrating lay navigators into the care team (Rocque GB, et al. JAMA Oncol. 2017 Jan 26. Epub ahead of print).
This observational study included Medicare beneficiaries with cancer who received care at participating CCN institutions from January 2012 through December 2015. The researchers used regression analysis to compare the changes in quarterly Medicare costs and healthcare use between patients who were navigated in the PCCP (N = 6214) and a propensity score–matched group of patients who did not receive navigation services (N = 6214). The 2 groups were matched on age at diagnosis, race, sex, cancer acuity, phase of care, comorbidity score, and preenrollment characteristics.
The primary end point was Medicare costs per beneficiary per quarter. The secondary end points included source of cost and healthcare resource utilization, which was defined by the number of quarterly emergency department visits, hospitalizations, or intensive care unit admissions.
The researchers found that the mean total costs decreased by $781.29 more per quarter per navigated patient compared with patients who did not receive navigation services, translating into an estimated $19-million reduction annually across the network. Inpatient and outpatient costs showed the largest between-group quarterly declines of $294 and $275 per patient, respectively. The researchers also observed decreases in resource use for the navigated group compared with the nonnavigated group, with emergency department visits, hospitalizations, and intensive care unit admissions declining by 6.0%, 7.9%, and 10.6% per quarter, respectively.
The researchers noted that PCCP is not sustainable under the current fee-for-service model. “This model has the potential to reach the Triple Aim of improved health care, better health, and lower costs and significantly enhanced health care delivery in the United States as health systems transition to value-based health care,” they concluded.
Adding Antiandrogen Therapy Improves Survival in Recurrent Prostate Cancer
Interim analysis from the NRG Oncology Radiation Therapy Oncology Group’s RTOG 9601 trial demonstrated a significant survival benefit in patients with prostate cancer recurrence after radical prostatectomy with the addition of the antiandrogen therapy bicalutamide for 24 months during and after salvage radiation therapy. Because prostate cancer can be a slowly progressive disease, longer-term follow-up was needed to determine if this combination therapy could further improve cancer control and prolong overall survival. In a new study, researchers reported the overall survival rate, which was the trial’s primary end point (Shipley WU, et al. N Engl J Med. 2017;376:417-428).
Conducted from 1998 to 2003, the double-blind, placebo-controlled, phase 3 study included 760 patients who, after removal of the prostate gland for localized cancer, had a biochemical recurrence, signified by an increase in prostate-specific antigen levels. Patients were randomized to bicalutamide 150 mg/day or to placebo for 24 months, along with 6.5 weeks of radiation therapy. The median follow-up among surviving patients was approximately 13 years.
At 12 years, the overall survival rate in the bicalutamide group was 76.3% compared with 71.3% in the placebo group. In addition to the overall survival benefit, the bicalutamide group had significantly lower rates of death from prostate cancer (5.8% vs 13.4%, respectively), distant metastases (14.5% vs 23.0%, respectively), and second biochemical recurrence (44.0% vs 67.9%, respectively) compared with the placebo group.
The researchers reported no significant between-group differences in the rates of early urinary, bowel, or hematologic reactions. The rates of grade 3 late genitourinary adverse events were only slightly higher in the bicalutamide group than in the placebo group (7.0% vs 6.0%, respectively), but rates of grade 4 adverse events were low in both groups (0.3% and 0.8%, respectively). However, 42.4% of patients receiving bicalutamide reported grade 1 gynecomastia, 23.6% reported grade 2, and 3.7% reported grade 3.
Since the trial was initiated, bicalutamide has largely been replaced by gonadotropin-releasing hormone (GnRH) agonist drugs. The researchers noted that the results still remain relevant. “Randomized trials involving patients with nonmetastatic disease have shown that high-dose bicalutamide and GnRH agonists have similar systemic anti-cancer efficacy,” they said. “As such, our trial presents proof of principle that the addition of hormone-based therapy to salvage radiation therapy is associated with significant and clinically important lower rates of prostate-cancer metastases and death.”