Continuous versus intermittent BRAF and MEK inhibition in patients with BRAF-mutated melanoma: a randomized phase 2 trial.

Preclinical modeling suggests that intermittent BRAF inhibitor therapy may delay acquired resistance when blocking oncogenic BRAFV600 in melanoma1,2. We conducted S1320, a randomized, open-label, phase 2 clinical trial (NCT02196181) evaluating whether intermittent dosing of the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib improves progression-free survival in patients with metastatic and unresectable BRAFV600 melanoma. Patients were enrolled at 68 academic and community sites nationally. All patients received continuous dabrafenib and trametinib during an 8-week lead-in period, after which patients with non-progressing tumors were randomized to either continuous or intermittent dosing of both drugs on a 3-week-off, 5-week-on schedule. The trial has completed accrual and 206 patients with similar baseline characteristics were randomized 1:1 to the two study arms (105 to continuous dosing, 101 to intermittent dosing). Continuous dosing yielded a statistically significant improvement in post-randomization progression-free survival compared with intermittent dosing (median 9.0 months versus 5.5 months, P = 0.064, pre-specified two-sided α = 0.2). Therefore, contrary to the initial hypothesis, intermittent dosing did not improve progression-free survival in patients. There were no differences in the secondary outcomes, including overall survival and the overall incidence of treatment-associated toxicity, between the two groups.

Incidence and Management of Olaratumab Infusion-Related Reactions.

PURPOSE: Olaratumab is a human monoclonal immunoglobulin G1 antibody against platelet-derived growth factor receptor-α. We report the nature and frequency of infusion-related reactions (IRRs) with olaratumab in clinical trials and postmarketing reports. METHODS: Data from patients exposed to olaratumab across nine clinical trials were reviewed for IRRs. Blood samples were also analyzed for pre-existing immunoglobulin E anti-galactose-α-1,3-galactose (anti-α-Gal) antibodies. RESULTS: In the clinical trials, IRRs were identified in 70 of 485 patients (14.4%). The most frequent symptoms included flushing, fever or chills, and dyspnea. For 68 of 70 patients (97.1%), the first IRR occurred during the first two cycles of treatment. Grade 3 or worse IRRs were reported in 11 patients (2.3%), all during the first infusion and usually within 15 minutes of the start of the infusion. One IRR-related fatality (0.2%) occurred in a nonpremedicated patient with grade 3 or worse cardiac comorbidities. There was an association between grade 3 or worse IRRs and pre-existing anti-α-Gal antibodies, with a trend toward higher IRR rates in US geographies known to have a higher prevalence of anti-α-Gal antibodies. IRRs in postmarketing reports were consistent in nature and severity with those in the clinical trials. CONCLUSION: Premedication with corticosteroids and antihistamines should occur in all patients before olaratumab infusion, as indicated in labels in the United States and the European Union. Patients receiving olaratumab should be monitored for IRRs in a setting where resuscitation equipment is available for the treatment of IRRs.

Programmed Cell Death-Ligand 1 (PD-L1) Expression in Anal Cancer.

OBJECTIVE: To evaluate the expression of programmed cell death-ligand 1 (PD-L1) in anal cancer. PATIENTS AND METHODS: In a retrospective cohort analysis, subjects with squamous cell carcinoma of the anal canal were tested for PD-L1 expression, then followed for recurrence and survival. Crude recurrence rates (CRRs), crude mortality rates (CMRs), and crude event rates (CERs) were assessed for PD-L1-dependent differences using Poisson regression. All 3 types of crude rate were expressed as the number that occurred per hundred person-years (hPY) of follow-up. RESULTS: Samples from 41 subjects were evaluated for PD-L1 expression; 23 (56%) were positive. Subjects with PD-L1-expressing versus PD-L1-negative tumors respectively had CRRs of 30.8 versus 12.1 recurrences/hPY (P=0.082), CMRs of 16.7 versus 12.0 deaths/hPY (P=0.47), and CERs of 39.2 versus 16.9 events/hPY (P=0.069). CONCLUSIONS: PD-L1 positivity was associated with worse CRR and CER, and marginally worse CMR. The effect on progression-free and overall survival needs to be validated in a study with a larger sample size.

A comparison of 12-gene colon cancer assay gene expression in African American and Caucasian patients with stage II colon cancer.

BACKGROUND: African American (AA) colon cancer patients have a worse prognosis than Caucasian (CA) colon cancer patients, however, reasons for this disparity are not well understood. To determine if tumor biology might contribute to differential prognosis, we measured recurrence risk and gene expression using the Oncotype DX® Colon Cancer Assay (12-gene assay) and compared the Recurrence Score results and gene expression profiles between AA patients and CA patients with stage II colon cancer. METHODS: We retrieved demographic, clinical, and archived tumor tissues from stage II colon cancer patients at four institutions. The 12-gene assay and mismatch repair (MMR) status were performed by Genomic Health (Redwood City, California). Student's t-test and the Wilcoxon rank sum test were used to compare Recurrence Score data and gene expression data from AA and CA patients (SAS Enterprise Guide 5.1). RESULTS: Samples from 122 AA and 122 CA patients were analyzed. There were 118 women (63 AA, 55 CA) and 126 men (59 AA, 67 CA). Median age was 66 years for AA patients and 68 for CA patients. Age, gender, year of surgery, pathologic T-stage, tumor location, the number of lymph nodes examined, lymphovascular invasion, and MMR status were not significantly different between groups (p = 0.93). The mean Recurrence Score result for AA patients (27.9 ± 12.8) and CA patients (28.1 ± 11.8) was not significantly different and the proportions of patients with high Recurrence Score values (≥41) were similar between the groups (17/122 AA; 15/122 CA). None of the gene expression variables, either single genes or gene groups (cell cycle group, stromal group, BGN1, FAP, INHBA1, Ki67, MYBL2, cMYC and GADD45B), was significantly different between the racial groups. After controlling for clinical and pathologic covariates, the means and distributions of Recurrence Score results and gene expression profiles showed no statistically significant difference between patient groups. CONCLUSION: The distribution of Recurrence Score results and gene expression data was similar in a cohort of AA and CA patients with stage II colon cancer and similar clinical characteristics, suggesting that tumor biology, as represented by the 12-gene assay, did not differ between patient groups.

MYC amplification in multiple marker chromosomes and EZH2 microdeletion in a man with acute myeloid leukemia.

The role of MYC and EZH2 in acute myeloid leukemia (AML) pathogenesis is poorly understood. Herein we present a case of AML with MYC amplification in marker chromosomes and a microdeletion of chromosome 7 below cytogenetic resolution. The karyotype of the patient's bone marrow aspirate showed three to five marker chromosomes in all dividing cells without other structural or numerical chromosomal abnormalities. Analysis by fluorescence in situ hybridization (FISH) with a probe specific for the human MYC gene revealed amplification of the oncogene localized to the marker chromosomes. Using whole genome single nucleotide polymorphism (SNP) microarray analysis, an approximately 4.4 Mb amplicon containing the MYC gene was identified with an estimated amplification of about 30 copies per leukemic cell and, thus, an average of about 8 copies per marker chromosome. A 6.4 Mb hemizygous microdeletion of chromosome 7 within band q36.1 was also found by SNP microarray analysis in a cellular-equivalent dosage of 50%. The microdeletion spans multiple genes, including EZH2, a gene with well-known cancer association. No mutation was found in the remaining EZH2 allele by next generation gene sequencing. The combination of MYC amplification and EZH2 deletion, which has not been described previously in AML, may suggest a synergistic role of the two oncogenes in the pathogenesis of the patient's acute leukemia.

Bevacizumab and erlotinib in previously untreated inoperable and metastatic hepatocellular carcinoma.

PURPOSE: To evaluate the combination of erlotinib and bevacizumab in subjects with hepatocellular carcinoma (HCC) who are not candidates for local therapy. PATIENTS AND METHODS: Twenty-one subjects with metastatic or inoperable HCC who had not received local or systemic therapy were treated with 15 mg/kg bevacizumab every 3 weeks and a daily dose of 150 mg oral erlotinib. The primary endpoint was progression-free survival (PFS) at 27 weeks. The secondary endpoints were median time to progression and median overall survival. RESULTS: Twenty-one subjects were enrolled. Eighteen were evaluable for the primary endpoint; all subjects were evaluable for toxicity. The median age was 60 years (range, 33 to 81 y). Five subjects (28%) were progression free at 27 weeks (90% confidence interval (CI), 12%-50%). Median time to progression was 2.57 months (95% CI, 2.13-4.20 mo). Median overall survival was 8.33 months (95% CI, 5.73-13.97 mo). Two subjects withdrew consent, and 1 subject did not have adequate baseline scans. CONCLUSIONS: The 28% progression-free survival rate at 27 weeks was not significantly higher than the recent historical control rate of 20% observed on the placebo arm of the Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol trial (P=0.28). The combination of bevacizumab and erlotinib does not appear to have sufficient efficacy in patients with unresectable and metastatic HCC not amenable to local therapy, and may not warrant further investigation. However, this could be evaluated as an alternative to those intolerant to sorafenib therapy.

SWOG 0514: a phase II study of sorafenib in patients with unresectable or metastatic gallbladder carcinoma and cholangiocarcinoma.

OBJECTIVES: Gallbladder and cholangiocarcinomas represent a heterogeneous group of malignant diseases that commonly present at an advanced stage and have limited therapeutic options. Based on the role of the Ras-Raf-Mek-Erk pathway and the VEGF axis in biliary carcinomas, we conducted a phase II study of sorafenib in patients with advanced biliary cancers. METHODS: Eligible patients had no prior therapy for metastatic or unresectable disease. Sorafenib was administered at 400 mg po twice daily continuously. RESULTS: The study was terminated after the first stage of accrual due to failure to meet the primary objective. A confirmed response rate of 0% (0%-11%) was observed. Thirty-nine percent of patients demonstrated stable disease (including 2 with unconfirmed PR). PFS was 3 months (95% CI: 2-4 months) and OS 9 months (95% CI: 4-12 months). The most common grade 3 and 4 toxicities included hand-foot skin reaction (13%), bilirubin elevation (13%), venous thromboembolism (10%), AST/ALT elevation (10%) and elevated alkaline phosphatase (10%). CONCLUSION: While treatment with sorafenib did not result in objective responses, patients with biliary cancers receiving this drug had some therapeutic benefit. Additional studies with sorafenib in combination with chemotherapy or other targeted agents may be warranted.

Heparin-induced skin necrosis associated with thrombocytopenia and acquired protein C and protein S deficiency.

We have described a patient with colon cancer and liver metastases who developed heparin-induced thrombocytopenia and skin necrosis. We believe that the skin necrosis caused by the heparin/platelet factor 4 antibody was exacerbated by the acquired protein C and protein S deficiency. After the heparin was discontinued and infection treated, the skin necrosis and thrombocytopenia resolved. This case illustrates the fact that, in patients with heparin-induced skin necrosis, a search must be undertaken for an underlying pro-thrombotic state, which may precipitate the microthrombosis responsible for skin necrosis. We could not find any previous case reports of heparin-induced skin necrosis associated with isolated protein C deficiency, or combined protein C and protein S deficiency.

Thiazolidinediones and the risk of lung, prostate, and colon cancer in patients with diabetes.

PURPOSE: Peroxisome proliferator-activated receptor gamma (PPARgamma) mediates cell cycle arrest and adipocyte differentiation; has tumor suppressor activity in liposarcoma, lung, and prostate cancers; and suppresses colonic polyp formation in adenomatous polyposis coli (APC)min/+ mice. To assess the influence of thiazolidinediones (TZDs), which are PPAR ligands used to treat diabetes mellitus, a retrospective analysis of a database from 10 Veteran Affairs medical centers was conducted. PATIENTS AND METHODS: Data on male patients 40 years and older diagnosed to have diabetes mellitus between 1997 and 2003 were obtained from the Veterans Integrated Services Network 16 (VISN 16) data warehouse. Subsequent diagnoses of colorectal, lung, and prostate cancer and use of TZD, other antidiabetic agents, and insulin were identified. Cox regression with time-dependent covariates was used to estimate the association between TZD use and cancer risk. Relative risks were adjusted for confounders (age, race/ethnicity, body mass index, use of insulin, and other oral antidiabetic agents). RESULTS: Of 87,678 individuals, 1,137 had colorectal cancer, 3,246 had prostate cancer, and 1,371 had lung cancer. We observed a 33% reduction in lung cancer risk among TZD users compared with nonusers after adjusting for confounder interactions (relative risk, 0.67; 95% CI, 0.51 to 0.87). The risk reduction for colorectal and prostate cancers did not reach statistical significance. CONCLUSION: TZD use was associated with reduced risk of lung cancer. Further studies are warranted to confirm our findings.

Racial differences in the outcome of patients with colorectal carcinoma.

BACKGROUND: African-American (AA) patients with colorectal carcinoma have a worse prognosis compared with Caucasians. To analyze the causes of this disparity in survival, a retrospective study of patients with colorectal carcinoma was undertaken. The impact of treatments received and the role of socioeconomic factors such as income, education, and poverty levels were studied. METHODS: A retrospective analysis of patients with colorectal carcinoma at a single institution was conducted. The overall survival of AA and Caucasians, stage at presentation, treatment received, and socioeconomic factors were analyzed using the institutional tumor registry and 1990 census data. RESULTS: The overall survival of AA patients was worse compared with Caucasians, both due to all causes (P < 0.001) and cancer-related deaths (P < 0.001). The relative risk of death due to all causes was 1.4 (95% confidence interval [CI] 1.2-1.8) for AA, 4.3 for patients with Stage IV disease (95% CI 3.2-5.7), and 2.3 for patients not undergoing surgery (95% CI 1.7-3.1). After multivariate adjustment for gender, site, socioeconomic factors, and therapeutic modalities, the relative risks for death were 1.5 (95% CI 1.2) for AA, 1.4 (95% CI 1.1-1.7) for patients 60 years of age or older, and 4.2 (95% CI 3.4-5.2) for Stage IV disease. The survival difference between AA and Caucasians was not influenced by income, poverty level, and education. African Americans were treated less frequently with chemotherapy and radiation therapy compared with their Caucasian counterparts. CONCLUSIONS: African American patients with colorectal carcinoma have a poorer prognosis compared with Caucasians. This discrepancy may be due to decreased utilization of chemotherapy and radiation therapy. Socioeconomic factors and lack of access to health care do not entirely explain the worse prognosis of AA. These factors should be identified and dealt with to improve the health care of AA patients with various malignant disorders.

Irinotecan/thalidomide in metastatic colorectal cancer.

The prognosis for patients with metastatic colorectal cancer is poor. Use of irinotecan (CPT-11, Camptosar) results in modest response rates of approximately 20% in refractory patients diagnosed with this advanced stage of disease and offers a side-effect profile that improves on that of previous standard treatments. Thalidomide (Thalomid) has antiangiogenic properties, and angiogenesis has been shown to influence the outcome of colon cancer patients. A good response rate and acceptable tolerability regarding gastrointestinal effects were demonstrated in a pilot study of the irinotecan/thalidomide combination in patients with metastatic colorectal cancer. This combination is being assessed at the University of Arkansas for Medical Sciences as second-line therapy in a phase II trial. Patients with metastatic colorectal cancer are receiving 350 mg/m2 of irinotecan every 3 weeks plus 400 mg/m2/d of thalidomide. Preliminary response and safety data are presented for 18 enrolled patients.