Predictors of survival outcomes in phase 1 relapsed or refractory multiple myeloma patients.

BACKGROUND: The categories of the International Myeloma Working Group (IMWG) response criteria for multiple myeloma are based on the magnitude of the change in paraprotein and the normalization of the free light chain ratio (rFLC). However, the relationship between the response by these biomarkers and clinical outcomes has not been validated with novel compounds in the phase 1 setting. Early response predictors may have prognostic value and speed development plans for new agents. METHODS: The relationship between biomarkers of response and clinical outcomes was examined in 87 relapsed or refractory multiple myeloma patients enrolled in nontransplant phase I clinical trials from January 2004 through November 2011 at 4 time landmarks. Progression-free survival (PFS) was the primary outcome, and overall survival (OS) was also assessed. RESULTS: The normalization of rFLC within 4 months predicted improvement in PFS (11.3 vs 2.8 months, P = .038), whereas the normalization of rFLC within 12 months predicted improvement in PFS (6.1 vs 2.8 months, P = .015) and OS (45 vs 17.4 months, P = .002). The magnitude of response in paraprotein predicted and correlated linearly with PFS at all time landmarks (R(2) = 0.703-0.943) when it was assessed with 2 different boundaries. CONCLUSIONS: These findings suggest that the normalization of rFLC and the magnitude of response are viable biomarkers for surrogate endpoints in early-phase clinical trials, validate the use of current IMWG response criteria in the phase 1 setting, and support the use of these biomarkers for drug development endpoints.

Current status and future directions of the immune checkpoint inhibitors ipilimumab, pembrolizumab, and nivolumab in oncology.

OBJECTIVE: To provide the clinician with an update and the current status and future direction of approved immune checkpoint inhibitors (ICIs) in oncology. DATA SOURCES: A PubMed search from January 1, 1966 to March 13, 2015 was performed using the key terms ipilimumab, pembrolizumab, lambrolizumab, nivolumab, immune checkpoint inhibitor, MDX-010, MDX-101, BMS-734016, MK-3475, SCH 900475, MDX-1106, BMS-936558, ONO-4538, CTLA-4, PD-1, or PD-L1 and cancer, oncology, or neoplasm. Additional references were identified from the investigators(') personal files, recent oncology meetings, review articles, clinical guidelines, and package inserts. STUDY SELECTION AND DATA EXTRACTION: All English-language clinical trials assessing the safety and efficacy of ipilimumab, nivolumab, and pembrolizumab in cancer were considered. The PubMed search resulted in 215 trials; 33 met inclusion criteria. A further 28 trials were identified from the above sources; 61 trials from 2005 to 2015 were included. We consolidated and clarified treatment recommendations for the management of immune-related adverse events (irAEs), assessed response criteria, and calculated the clinical utility of leading tumor profiling options. DATA SYNTHESIS: Ipilimumab and nivolumab, but not pembrolizumab, have an overall survival (OS) advantage over chemotherapy first line in unresectable/metastatic melanoma. Nivolumab has an OS advantage versus chemotherapy in second-line squamous non-small-cell lung cancer. Data in other settings are promising. Nivolumab and pembrolizumab are better tolerated than ipilimumab. Further validation of response criteria is needed. Tumor profiling to predict clinical benefit is premature but promising. CONCLUSIONS: The treatment landscape in oncology is quickly evolving with the advent of ICIs.

Subcutaneous versus intravenous bortezomib: efficiency practice variables and patient preferences.

BACKGROUND: Subcutaneous bortezomib is noninferior in efficacy to intravenous bortezomib and is associated with a lower incidence of neuropathy in the treatment of multiple myeloma. However, there are no data assessing the effect of subcutaneous bortezomib administration on practice variables or patient preferences. OBJECTIVE: To quantify the difference in efficiency practice variables and patient preferences regarding subcutaneous versus intravenous bortezomib administration in patients with multiple myeloma. METHODS: This study was divided into 2 parts consisting of mutually exclusive patients: a retrospective efficiency study and a survey study. Patients' medical records were reviewed for efficiency data measures including length of infusion chair time and overall infusion center visit time in patients who received at least 6 doses of bortezomib. Patients who received at least 1 dose each of subcutaneous and intravenous administration were surveyed regarding preference, satisfaction, injection site reactions, and quality of life measures. A database was used to identify eligible patients for each portion of the study. RESULTS: A review of 92 medical records demonstrated a 38% reduction in chair time (143 vs 89 minutes; p < 0.001) and a 27% reduction in infusion center visit time (169 vs 123 minutes; p < 0.001) with subcutaneous versus intravenous administration of bortezomib. Of 47 eligible patients, 60% (28) completed the survey; 68% (19; p = 0.0002) of these patients preferred and were more satisfied with subcutaneous bortezomib administration. The overall incidence of injection site reactions was 39% (11) in the surveyed population and was not significantly different between the 2 preference groups. Limitations of the study include single-center design, small sample size, and nonvalidated survey. CONCLUSIONS: Subcutaneous administration of bortezomib is more time efficient for the patient and institution and is preferred by patients compared to intravenous bortezomib.

Safety and efficacy of extended dosing intervals of denosumab in patients with solid cancers and bone metastases: a retrospective study.

AIM: More than half of patients with breast, lung, or prostate cancer who have bone metastases have evidence of skeletal-related events (SREs). Denosumab is a fully human monoclonal antibody that binds to and neutralizes receptor activator of nuclear factor kappa-B ligand (RANKL) on osteoblasts and their precursors. The United States Food and Drug Administration (FDA)-approved dose of denosumab is 120 mg every 4 weeks; however, other schedules have been used in practice for patient convenience. Evidence for the safety and efficacy of alternative dosing intervals is lacking. PATIENT & METHODS: Adult patients with solid cancers and bone metastases who received at least two doses of denosumab 120 mg were reviewed. Patients were grouped based on an average denosumab dosing interval of <5 weeks (short-interval) versus 5-11 weeks (medium-interval) versus ⩾12 weeks (long-interval). The primary outcome was the time to first SRE while on denosumab between the short- and medium-interval groups. The secondary outcomes were overall survival (OS), efficacy comparisons between the other groups, and safety events. RESULTS: There was no significant difference in median time to first SRE between the short- and medium-interval denosumab groups [33.2 versus 28.4 months, hazard ratio (HR): 1.13, 95% confidence interval (CI): 0.66-1.92, p = 0.91] or the medium- and long-interval dosing groups (28.4 versus 32.2 months, HR: 1.15, 95% CI: 0.66-2.01, p = 0.62). Median OS was not found to differ significantly between any of the groups. There were significantly more hospitalizations in the short-interval dosing group than the other groups (55.2% versus 33.8% versus 30.4%, p < 0.001). CONCLUSION: Extending denosumab dosing intervals does not appear to negatively impact time to first SRE and is associated with fewer hospitalizations in real-world patients with solid cancers and bone metastases.

Comparison of rates of adherence to oral chemotherapy medications filled through an internal health-system specialty pharmacy vs external specialty pharmacies.

PURPOSE: The primary objective of the study described here was to compare rates of patient adherence to anticancer medications filled at an internal health system specialty pharmacy (HSSP) vs external specialty pharmacies. The primary outcome was the medication possession ratio (MPR), and the secondary outcomes included proportion of days covered (PDC), and time to treatment (TTT). METHODS: A retrospective chart review was conducted to compare the MPR, PDC, and TTT for patients who received oral anticancer therapy using prescriptions claim data. A t test or Wilcoxon test was used to explore the effect of demographic and other factors on adherence and TTT. A multiple regression model with backward elimination was used to analyze significant factors to identify covariates significantly associated with the outcomes. RESULTS: Of the 300 patients screened for study inclusion, 204 patients whose records had complete MPR and PDC data and 164 whose records had TTT data were included in the analysis. There were significant between-group differences in mean MPR and mean PDC with patient use of the HSSP vs external pharmacies (1.00 vs 0.75 [P < 0.001] and 0.95 vs 0.7 [P < 0.001], respectively). Pharmacy type (P = 0.024) and tumor type (P = 0.048) were significantly associated with TTT. CONCLUSION: The multiple regression analysis indicated that oncology patients who filled their anticancer medication precriptions at an internal HSSP at an academic medical center had significantly higher adherence, as measured by MPR and PDC, and quicker TTT than those who filled their prescriptions at an external specialty pharmacy.

Pembrolizumab for the treatment of PD-L1 positive advanced or metastatic non-small cell lung cancer.

The emergence of immune checkpoint inhibitors marked an important advancement in the development of cancer therapeutics. Pembrolizumab is a selective humanized IgG4 kappa monoclonal antibody that inhibits the programmed death-1 (PD-1) receptor, an integral component of immune checkpoint regulation in the tumor microenvironment. The drug is currently approved by the Food and Drug Administration for the treatment of advanced melanoma and metastatic squamous and nonsquamous non-small cell lung cancer (NSCLC). Several published studies demonstrate that single-agent pembrolizumab is safe and has efficacy in patients with NSCLC. Many ongoing protocols are investigating the role of pembrolizumab in combination with other agents in lung cancer and various other cancer types. We review the available data on pembrolizumab in NSCLC and examine the role of potential predictive biomarkers of response to therapy.

Taxanes: vesicants, irritants, or just irritating?

Several classes of antineoplastic agents are universally referred to as vesicants with ample supporting literature. However, the literature surrounding the taxanes is controversial. While the American Society of Clinical Oncology and Oncology Nursing Society Chemotherapy Administration Safety Standards and the Chemotherapy and Biotherapy Guidelines and Recommendations for Practice identify the risks of extravasation and the parameters surrounding the infusion of known vesicants, recommend administration sites for known agents, and recommend antidotes for particular extravasation cases, they fail to provide specific recommendations for the administration of individual taxanes, or a classification system for antineoplastic agents as vesicants, irritants, or inert compounds. There is also a lack of prescribing information regarding such recommendations. The lack of a formal classification system further complicates the accurate delineation of vesicant antineoplastic agents and subsequent appropriate intravenous administration and extravasation management. There are several factors that make the classification of taxanes as vesicants or irritants challenging. Comprehensive preclinical data describing potential mechanisms of tissue damage or vesicant-like properties are lacking. Furthermore, most case reports of taxane extravasation fail to include the parameters surrounding administration, such as the concentration of medication and duration of infusion, making it difficult to set parameters for vesicant potential. Subsequently, many practitioners default to central venous administration of taxanes without evidence that such administration minimizes the risk of extravasation or improves outcomes thereof. Here, we review briefly the data surrounding taxane extravasation and potential vesicant or irritant properties, classify the taxanes, and propose a spectrum for antineoplastic agent potential to cause tissue injury that warrants clinical intervention if extravasation occurs.