Cutaneous eruptions from ibrutinib resembling epidermal growth factor receptor inhibitor-induced dermatologic adverse events.

BACKGROUND: Ibrutinib is an oral inhibitor of Bruton tyrosine kinase that is approved by the United States Food and Drug Administration for several lymphoproliferative disorders and chronic graft-versus-host disease. OBJECTIVE: To characterize cutaneous eruptions arising from ibrutinib and highlight overlap with epidermal growth factor receptor (EGFR) inhibitor-induced dermatologic adverse events. METHODS: Single-center retrospective cohort of patients referred to the Skin Toxicities Program for treatment of cutaneous eruptions while taking ibrutinib. RESULTS: Among 19 patients, cutaneous eruptions manifested as facial-predominant papulopustular eruptions, petechiae, or ecchymoses, photosensitivity, panniculitis, xerosis, and clinical staphylococcal overgrowth. Most patients were able to continue ibrutinib therapy with focused treatment of their cutaneous toxicities. LIMITATIONS: This study represents cases at a single tertiary care center and is limited to patients referred for toxicity. CONCLUSIONS: With the exception of petechiae, the cutaneous toxicities of ibrutinib overlap with those associated with selective EGFR inhibitors. We observed that these reactions can be successfully managed using approaches for EGFR inhibitor-induced cutaneous adverse events.

A phase II study of cabozantinib alone or in combination with trastuzumab in breast cancer patients with brain metastases.

PURPOSE: To analyze the efficacy and tolerability of cabozantinib-a small molecule inhibitor of MET and VEGFR2-alone or with trastuzumab in patients with breast cancer brain metastases (BCBM). METHODS: This single-arm phase II study enrolled patients with new or progressive measurable BCBM into 3 cohorts: Cohort 1 (HER2-positive), Cohort 2 (hormone receptor-positive/HER2-negative), and Cohort 3 (triple-negative). Patients received cabozantinib 60-mg daily on a 21-day cycle. Cohort 1 added trastuzumab every 3 weeks and had a primary objective of central nervous system (CNS) objective response rate (ORR) by RECIST 1.1. Secondary objectives for all cohorts were progression-free survival, overall survival, toxicity, and changes in vascular parameters and circulating biomarkers. Cohorts 2 and 3 also had CNS ORR as a secondary objective. RESULTS: Thirty-six BCBM patients enrolled (cohort 1, n = 21; cohort 2, n = 7; cohort 3, n = 8), with a median age of 50. Patients had a median of 3 prior lines for metastatic disease (range 1-9). Treatments prior to enrollment included craniotomy (n = 4), whole brain radiation (n = 24) and stereotactic radiosurgery (n = 11). CNS ORR was 5% in cohort 1, 14% in cohort 2, and 0% in cohort 3. Most common grade 3/4 adverse events included elevations in lipase (11%), AST (8%), ALT (6%), hyponatremia (8%), and hypertension (6%). Cabozantinib increased plasma concentrations of CA-IX, soluble (s)MET, PlGF, sTIE-2, VEGF, and VEGF-D, and decreased sVEGFR2 and TNF-α and total tumor blood volume. CONCLUSIONS: Cabozantinib had insufficient activity in heavily pretreated BCBM patients. Biomarker analysis showed that cabozantinib had antiangiogenic activity and increased tissue hypoxia. TRIAL REGISTRATION: Clinicaltrial.gov registration: NCT02260531.

Risk of Serious Infections Associated with Biologic Agents in Juvenile Idiopathic Arthritis: A Systematic Review and Meta-Analyses.

OBJECTIVE: To assess whether treatment with biologic response modifying agents during clinical trial study periods increases the risk of serious infections in children with juvenile idiopathic arthritis (JIA). STUDY DESIGN: A systematic literature review using Medline, Embase, Cochrane library, and the clinical trial registry was performed up to July 2017. Random effects meta-analyses were used to compare rates of serious infections in children with JIA given biologic agents compared with controls, and the pooled relative risk calculated. Subanalyses were performed for different biologic agent classes. RESULTS: In total, 19 trials accounting for 21 individual studies were included (11 for tumor necrosis factor-alpha inhibitors [n = 814 patients], 3 for interleukin-6 inhibitors [n = 318], 6 for interleukin-1 inhibitors [n = 353], and 1 for selective T-lymphocyte costimulation modulators [n = 122]). Patients (68% female) had a mean age of 10.8 years. Seventeen serious infections were reported among 810 children receiving biologic agents and 15 among 797 controls. The most frequent infections were bronchopulmonary and varicella. No statistically significant difference in risk of serious infections was found between children receiving biologic agents compared with control groups (pooled relative risk = 1.13; 95% CI [0.63, 2.03]) during the trial study periods. The risk remained nonsignificant when evaluating the different classes of biologic agents separately. However, the analyses were underpowered to detect differences in the risk of serious infections overall or differences between classes of biologic agents. CONCLUSIONS: In this systematic review and meta-analyses, serious infections were uncommon and not significantly increased among patients with JIA receiving biologic agents compared with controls. However, the analyses were underpowered and study periods were relatively short. Ongoing careful monitoring for serious infections remains necessary for all patients with JIA, and particularly those receiving biologic agents.

Clinicopathologic features correlated with paradoxical outcomes in stage IIC versus IIIA melanoma patients.

Under current AJCC staging criteria, stage IIC patients paradoxically have worse outcomes than IIIA patients despite the lack of nodal metastatic disease. This study sought to identify additional clinicopathologic characteristics correlated with worse patient outcomes. Retrospective chart review of stage IIC and IIIA melanoma patients were evaluated between 1995 and 2011 with clinical follow-up through 2015. Records were reviewed for demographics, clinical characteristics, and tumor pathology. Fisher's exact test and Wilcoxon's rank-sum test were used to assess group differences. Clinicopathologic features were evaluated relative to overall survival (OS), time to distant metastases, and local/regional recurrence. Overall, 128 patients were included (45 stage IIC and 83 stage IIIA) with a median follow-up time of 5.7 years. Compared with stage IIIA patients, stage IIC patients were older, and their melanomas were more likely to be nodular, amelanotic, thicker, have higher mitotic rate, tumor lymphocytic infiltrate, no radial growth phase, and less likely to have associated precursor lesions. Stage IIC patients had shorter OS and time to distant metastases; multivariate regression revealed that older age (>55 years) and mitotic rate (>5 mitoses/mm) were independent predictors of OS. Melanomas in stage IIC disease may be biologically distinct from those that are seen in stage IIIA. While sentinel node biopsies remain the standard-of-care, these results suggest that clinicians may want to assess the clinicopathologic characteristics described above to aggressively counsel, screen for distant disease, and consider adjuvant therapy, in particular for older patients and higher mitotic rates in thicker primary tumors, regardless of nodal status.

Association of Dermatologist Density With the Volume and Costs of Dermatology Procedures Among Medicare Beneficiaries.

Importance: The persistent shortage of dermatologists in the United States affects access to care and patient outcomes. Objective: To characterize the effect of geographic variations in dermatologist density on the provision of dermatology procedures within Medicare. Design, Setting, and Participants: This was a cross-sectional study using the 2013 Medicare Provider Utilization and Payment Database. Dermatology-related procedures were defined by the top 50 billing codes accounting for more than 95% of procedures billed by dermatologists. Billing codes corresponding to evaluation and monitoring visits and dermatopathology were excluded. Total costs were estimated from the Centers for Medicare & Medicaid Services physician fee schedule, based on the nonfacility national payment amount with no modifiers. Nationally representative administrative database that includes 100% of charges billed by noninstitutional clinicians covered under Medicare Part B. A total of 10 391 dermatologists practicing within the 50 states and Washington, DC, were included. The Medicare-eligible population was defined as all persons 65 years or older. Exposures: Density of dermatologists, categorized into first (5.3 per 100 000 persons ≥65 years) through fifth (54.8 per 100 000 persons ≥65 years) quintiles. Main Outcomes and Measures: Utilization of dermatology procedures (mean volume per 100 000 persons ≥65 years) and total cost (mean amount billed per person ≥65 years) by clinician type across quintiles of dermatologist density. Results: In 2013, dermatologists billed Medicare for 28 million procedures costing $2.21 billion. Mean billed amount by dermatologists per person 65 years or older was $15.87 in the lowest-density quintile vs $92.02 in the highest-density quintile. This trend suggests that each interval increase of 10 dermatologists per 100 000 persons 65 years or older is correlated with a $14.81 increase in Medicare spending on dermatology procedures (95% CI, 8.28-21.34; P = .005). Utilization of these procedures differed among clinician types, with dermatologists largely performing destruction of premalignant lesions and PCPs primarily doing injections. Conclusions and Relevance: There is evidence of supply-sensitive variation in the provision of dermatology procedures for the Medicare-eligible population; higher dermatologist density is correlated with increased utilization of dermatology procedures and subsequent billed charges to Medicare. Further research is needed to determine the effect of such variations on outcomes and whether incentives can better align dermatologists with areas of clinical need.

Phase II study of tivantinib (ARQ 197) in patients with metastatic triple-negative breast cancer.

BACKGROUND: MET expression and activation appear to be important for initiation and progression of triple-negative breast cancer. Tivantinib (ARQ 197) is an orally administered agent that targets MET, although recent preclinical data suggests the agent may have mechanisms of action that are independent of MET signaling. We conducted a phase 2 study of tivantinib monotherapy in patients with metastatic triple-negative breast cancer. METHODS: Patients with metastatic triple-negative breast cancer who had received 1 to 3 prior lines of chemotherapy in the metastatic setting were enrolled into this two-stage, single arm phase 2 study. Treatment consisted of twice daily oral dosing of tivantinib (360 mg po bid) during a 21-day cycle. Patients underwent restaging scans at 6 weeks, and then every 9 weeks. Tumor biomarkers that might predict response to tivantinib were explored. RESULTS: 22 patients were enrolled. The overall response rate was 5 % (95 % CI 0-25 %) and the 6-month progression-free survival (PFS) was 5 % (95 % CI 0-25 %), with one patient achieving a partial response (PR). Toxicity was minimal with only 5 grade ≥3 adverse events (one grade 3 anemia, one grade 3 fatigue, and 3 patients with grade 3/4 neutropenia). CONCLUSION: This study represents the first evaluation of tivantinib for the treatment of metastatic triple-negative breast cancer. These results suggest that single agent tivantinib is well tolerated, but did not meet prespecified statistical targets for efficacy.