Randomized, Double-Blind, Placebo-Controlled, Global Phase III Trial of Talimogene Laherparepvec Combined With Pembrolizumab for Advanced Melanoma.

PURPOSE: The combination of talimogene laherparepvec (T-VEC) and pembrolizumab previously demonstrated an acceptable safety profile and an encouraging complete response rate (CRR) in patients with advanced melanoma in a phase Ib study. We report the efficacy and safety from a phase III, randomized, double-blind, multicenter, international study of T-VEC plus pembrolizumab (T-VEC-pembrolizumab) versus placebo plus pembrolizumab (placebo-pembrolizumab) in patients with advanced melanoma. METHODS: Patients with stage IIIB-IVM1c unresectable melanoma, naïve to antiprogrammed cell death protein-1, were randomly assigned 1:1 to T-VEC-pembrolizumab or placebo-pembrolizumab. T-VEC was administered at ≤ 4 × 106 plaque-forming unit (PFU) followed by ≤ 4 × 108 PFU 3 weeks later and once every 2 weeks until dose 5 and once every 3 weeks thereafter. Pembrolizumab was administered intravenously 200 mg once every 3 weeks. The dual primary end points were progression-free survival (PFS) per modified RECIST 1.1 by blinded independent central review and overall survival (OS). Secondary end points included objective response rate per mRECIST, CRR, and safety. Here, we report the primary analysis for PFS, the second preplanned interim analysis for OS, and the final analysis. RESULTS: Overall, 692 patients were randomly assigned (346 T-VEC-pembrolizumab and 346 placebo-pembrolizumab). T-VEC-pembrolizumab did not significantly improve PFS (hazard ratio, 0.86; 95% CI, 0.71 to 1.04; P = .13) or OS (hazard ratio, 0.96; 95% CI, 0.76 to 1.22; P = .74) compared with placebo-pembrolizumab. The objective response rate was 48.6% for T-VEC-pembrolizumab (CRR 17.9%) and 41.3% for placebo-pembrolizumab (CRR 11.6%); the durable response rate was 42.2% and 34.1% for the arms, respectively. Grade ≥ 3 treatment-related adverse events occurred in 20.7% of patients in the T-VEC-pembrolizumab arm and in 19.5% of patients in the placebo-pembrolizumab arm. CONCLUSION: T-VEC-pembrolizumab did not significantly improve PFS or OS compared with placebo-pembrolizumab. Safety results of the T-VEC-pembrolizumab combination were consistent with the safety profiles of each agent alone.

Incidence of skeletal-related events among multiple myeloma patients in the United States at oncology clinics: Observations from real-world data.

Skeletal-related events (SREs) are common bone complications in multiple myeloma (MM). However, there are few real-world reports of their incidence. In this study, a database of oncology electronic health records was linked to administrative claims data. Patients identified were aged ≥18 years and newly diagnosed with MM, had ≥1 clinic visit within 1 month of diagnosis, and ≥1 year of follow-up after diagnosis. The study period was January 1, 2011 to December 31, 2016. 343 patients were included, 35% of whom had a baseline history of any SRE. During a median follow-up of 25.7 months, 34% of patients experienced SREs after diagnosis. Median time to SRE was 167 days. Among patients experiencing an SRE, 68% had an SRE within the first year. The incidence rate of SREs at 1 year following MM diagnosis for patients with baseline history was 103/100 person-years (PY) versus 16/100PY for patients without baseline history. SRE incidence rates within 3 months of initiating a line of therapy increased with subsequent lines (line 1: 81/100PY, line 2: 118/100PY, line 3: 150/100PY). Risk of SREs was similar across different anti-MM regimens, including proteasome inhibitor-based regimens. These results highlight the importance of continued surveillance and management of MM-associated bone disease.

Role of the RANK/RANKL Pathway in Multiple Myeloma.

Receptor activator of nuclear factor-kappa B (RANK) and its ligand, RANKL, are expressed in a variety of tissues throughout the body; their primary role is in the regulation of bone remodeling and development of the immune system. Consistent with these functions, evidence exists for a role of RANK/RANKL in all stages of tumorigenesis, from cell proliferation and carcinogenesis to epithelial-mesenchymal transition to neoangiogenesis and intravasation to metastasis to bone resorption and tumor growth in bone. Results from current studies also point to a role of RANK/RANKL signaling in patients with multiple myeloma, who have increased serum levels of soluble RANKL and an imbalance in RANKL and osteoprotegerin. Current therapies for patients with multiple myeloma demonstrate that RANKL may be released by tumor cells or osteoprogenitor cells. This article will review currently available evidence supporting a role for RANK/RANKL signaling in tumorigenesis, with a focus on patients with multiple myeloma.

National trends in spending on and use of oral oncologics, first quarter 2006 through third quarter 2011.

Oral prescription drugs are an increasingly important treatment option for cancer. Yet contemporaneous US trends in spending on anticancer drugs known as oral oncologics have not been described. Using nationally representative data, we describe trends in national spending on and use of forty-seven oral oncologics between the first quarter of 2006 and the third quarter of 2011. Average quarterly national spending on oral oncologics increased 37 percent, from $940.3 million to $1.4 billion in 2012 dollars, a significant change. Average quarterly use of oral oncologics in the same time period measured in extended units increased at a significant pace but more slowly than spending (10 percent). Within this broader trend, differences in spending among categories of oral oncologics were observed. High levels of and increases in both spending and use were concentrated among new brand-name and patent-protected oral oncologics, including second-generation tyrosine kinase inhibitors used to treat chronic myelogenous leukemia. Decreased spending but increased use was observed among oral oncologics that lost patent protection during the study period and were available in generic form, including hormonal therapies used to treat breast and prostate cancers. Spending on new and patent-protected oral oncologics and associated price increases are significant drivers of increased spending.

Factors associated with compliance to adjuvant hormone therapy in Black and White women with breast cancer.

BACKGROUND: Studies have demonstrated lower rates of breast cancer survival for Black versus White women. Factors implicated include later stages at diagnosis, differences in tumor biology, and lower compliance rates to adjuvant hormone therapy (AHT) among Black women with hormone sensitive breast cancer. We examined factors associated with compliance to AHT among Black and White women with invasive breast cancer. METHODS: Women with estrogen receptor positive (ER+), non-metastatic breast cancer were identified by the cancer registry at the University of Chicago Hospital and asked to complete a mail-in survey. Compliance was defined by self-reported adherence to AHT ≥80% at the time of the survey plus medical record verification of persistence (completion of 5 years of AHT). Logistic regression was used to determine factors associated with compliance to AHT. RESULTS: 197 (135 White and 62 Black) women were included in the analysis. 97.4% of patients reported adherence to therapy. 87.4% were found to be persistent to therapy. Overall compliance was 87.7% with no statistically significant racial difference seen (87.9% in White and 87.0% in Black, P = 0.87). For both Black and White women, compliance was strongly associated with both perceived importance of AHT (OR =2.1, 95% CI:1.21-3.68,P = 0.009) and the value placed on their doctor's opinion about the importance of AHT (OR = 4.80, 95% CI: 2.03-11.4, P < 0.001). CONCLUSIONS: In our cohort of Black and White women, perceived importance of AHT and the degree to which they valued their doctor's opinion correlated with overall compliance. This suggests that Black and White women consider similar factors in their decision to take AHT.

Effects of vascular endothelial growth factor signaling inhibition on human erythropoiesis.

Inhibition of vascular endothelial growth factor (VEGF) signaling increases red blood cell (RBC) counts, and erythropoiesis markers have been proposed to guide antiangiogenic therapy in humans. We analyzed RBC measurements in patients enrolled in three studies: a phase II trial of axitinib in thyroid cancer; a study of sorafenib in advanced solid tumors; and a randomized trial of fluorouracil, hydroxyurea, and radiation with and without bevacizumab for head and neck cancer. In the sorafenib trial, plasma erythropoietin concentrations were measured at baseline, day 8, and day 35. Over the first 84 days of treatment, RBC counts increased for each day on sorafenib (2.7 M/µL [95% confidence interval (CI), 1.5-3.9]) and axitinib (4.3 M/µL [95% CI, 2.2-6.5]). RBCs declined over the first 68 days of cytotoxic chemoradiotherapy alone (-12.8 M/µL per day [95% CI, -15.7 to -9.8]) but less so with added bevacizumab (-7.2 M/µL per day [95% CI, -9.5 to -4.9]). Erythropoietin levels increased, on average, by 9.5 mIU/mL between day 8 and day 35 of sorafenib exposure. No significant relationships between elevations in RBCs and changes in volume status or blood pressure or between elevations in erythropoietin and smoking status were found. VEGF signaling inhibition is associated with increased RBC and erythropoietin production in humans. The effects of these changes are subtle at physiologic doses and are unlikely to be clinically useful biomarkers for guiding the administration of or predicting treatment responses to VEGF pathway inhibitors.