Patients with advanced pancreatic cancer have a poor prognosis and there have been no improvements in survival since the introduction of gemcitabine in 1996. Pancreatic tumors often overexpress human epidermal growth factor receptor type 1 (HER1/EGFR) and this is associated with a worse prognosis. We studied the effects of adding the HER1/EGFR-targeted agent erlotinib to gemcitabine in patients with unresectable, locally advanced, or metastatic pancreatic cancer.
4609 Background: The epidermal growth factor receptor (EGFR) is a potentially important target in PC. Benefit from erlotinib (Tarceva), an oral EGFR tyrosine kinase inhibitor has been associated with the presence of a skin rash. The purpose of this study was to determine the efficacy of erlotinib, dosed to achieve a rash, in patients (pts) with PC. Methods: Erlotinib was given at an initial dose of 150 mg/day to eligible pts with locally advanced (LA) or metastatic PC who had progressed or were unable to tolerate gemcitabine-based chemotherapy. The dose of erlotinib was increased by 50mg every 2 weeks (maximum 300 mg/day) until > grade 1 rash (CTCAE v 3.0) or other dose-limiting toxicities occurred. Erlotinib pharmacokinetic (PK) studies were performed. Baseline tumor tissue was collected for analysis of Kras mutations, EGFR by IHC and FISH. The primary endpoint of this two- stage phase II trial was prolonged disease control (PR + SD > 8 wks) with a rate of >20% assumed to be significant . Results: Fifty pts were accrued (median age 61, M:F = 25:25, ECOG 0:1:2 = 5:41:4, LA:Metastatic = 5:45, prior gemcitabine none:adjuvant:palliative = 2:16:35). 47 and 40 pts were evaluable for toxicity and response, respectively. Dose-escalation to 200–300 mg of erlotinib was possible in 9 pts. Most common treatment adverse events (TAEs) of any grade were: rash (35 pts, 74.5%), diarrhea (18 pts, 38.3 %), and fatigue (8 pts, 17%). Grade 3+ TAEs were rash in 2 pts and diarrhea in 2 pts. Best response was SD in 14 pts, 0.35 (95% CI: 0.2–0.5). Prolonged disease control (SD > 8 wks) was observed in 10/40 evaluable pts, 0.25 (95% CI: 0.12–0.38), which met the primary study endpoint. Median TTP was 1.6 mo (95% CI:1.6–2.1), mOS 4.1 mo (95% CI:3.2–7.3), and 6 mo OS rate was 39% (95%CI: 24–61%). PK and correlative data are being analyzed and will be presented. Conclusions: Erlotinib is associated with prolonged stable disease in a subset of pts with advanced refractory PC. Dose escalation in the absence of toxicity is feasible and safe. [Table: see text]
The National Cancer Institute of Canada Clinical Trials Group CO.17 study showed that patients with advanced colorectal cancer had improved overall survival when cetuximab, an epidermal growth factor receptor-targeting antibody, was given in addition to best supportive care. We conducted a cost-effectiveness analysis using prospectively collected resource utilization and health utility data for patients in the CO.17 study who received cetuximab plus best supportive care (N = 283) or best supportive care alone (N = 274).Direct medical resource utilization data were collected, including medications, physician visits, toxicity management, blood products, emergency department visits, and hospitalizations. Mean survival times for the study arms were calculated for the entire population and for the subset of patients with wild-type KRAS tumors over an 18- to 19-month period. All costs were presented in 2007 Canadian dollars. One-way and probabilistic sensitivity analysis was used to determine the robustness of the results. Cost-effectiveness acceptability curves were determined. The 95% confidence intervals (CIs) for the incremental cost-effectiveness ratios and the incremental cost-utility ratios were estimated by use of a nonparametric bootstrapping method (with 1000 iterations).For the entire study population, the mean improvement in overall and quality-adjusted survival with cetuximab was 0.12 years and 0.08 quality-adjusted life-years (QALYs), respectively. The incremental cost with cetuximab compared with best supportive care was $23,969. The incremental cost-effectiveness ratio was $199,742 per life-year gained (95% CI = $125,973 to $652,492 per life-year gained) and the incremental cost-utility ratio was $299,613 per QALY gained (95% CI = $187,440 to $898,201 per QALY gained). For patients with wild-type KRAS tumors, the incremental cost with cetuximab was $33,617 and mean gains in overall and quality-adjusted survival were 0.28 years and 0.18 QALYs, respectively. The incremental cost-effectiveness ratio was $120,061 per life-year gained (95% CI = $88,679 to $207,075 per life-year gained) and the incremental cost-utility ratio was $186,761 per QALY gained (95% CI = $130,326 to $334,940 per QALY gained). In a sensitivity analysis, cetuximab cost and patient survival were the only variables that influenced cost-effectiveness.The incremental cost-effectiveness ratio of cetuximab over best supportive care alone in unselected advanced colorectal cancer patients is high and sensitive to drug cost. Incremental cost-effectiveness ratios were lower when the analysis was limited to patients with wild-type KRAS tumors.
2015 Background: Anthracyclines are widely used for the treatment of breast cancer. Unlike doxorubicin, the major mechanism of epirubicin inactivation is metabolism to inactive glucuronides by uridine glucuronosyltransferase (UGT) 2B7. A polymorphism has been discovered at position -161 T to C in the enhancer region which correlated with efficacy of morphine glucuronidation (Sawyer et al. Clin Pharmcol Ther 2003). Methods: We have carried out a prospective pharmacogenetic study of epirubicin metabolism in M0 breast cancer patients treated with adjuvant or neoadjuvant FEC100 (5-fluorouracil 500 mg/m2, Epirubicin 100 mg/m2 and cyclophosphamide 500 mg/m2) given every 3 weeks. Patients did not receive prophylactic G-CSF. Drug levels were drawn at 1 and 24 hours. Patients were followed during cycle 1 for toxicity, graded according to the NCIC CTC criteria. To date 102 patients have been enrolled to date out of a planned sample of 120. Patient characteristics-median (range): age 50 (28 - 67), sex 101 F/ 1 M, baseline AST 22 U/L (13–66), ALT 21 U/L (5–90), bilirubin 7 μmol/L (2–24), creatinine 73 μmol/L (51 - 126). Results: 24 patients were TT homozygotes, 55 were CT heterozygotes, and 23 were CC homozygotes. There was no relationship between nausea, vomiting or mucositis and UGT2B7 genotype. The mean neutrophil survival fraction was 14%, 11% and 8% for TT, CT, and CC genotypes (p=0.3, ANOVA test). There was a trend for increased grade 3/4neutropenia in patients having at least one deficient allele (i.e. CT or CC) vs. wild type homozygous (TT) (p=0.1, Chi square test). Patients with a deficient allele (CT or CC) were at increased risk for grade 3/4 leucopenia compared to TT homozygotes (p=0.01, Chi square test). Conclusions: The preliminary analysis of this prospective pharmacogenetic study suggested that the UGT2B7 -161 C/T SNP predicts for grade 3/4 leucopenia in women treated with FEC100. Studies of this UGT2B7 polymorphism as a predictor of epirubicin toxicity and efficacy are warranted. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer Pfizer Pfizer
'%3e%3ccircle r='20' fill='%23008'/%3e%3ccircle r='17.5' fill='%23fff'/%3e%3ccircle r='3.5' fill='%23008'/%3e%3cg id='d'%3e%3cg id='c'%3e%3cg id='b'%3e%3cg id='a' fill='%23008'%3e%3ccircle r='.875' transform='rotate(7.5 -8.75 133.5)'/%3e%3cpath d='M0 17.5.6 7 0 2l-.6 5L0 17.5z'/%3e%3c/g%3e%3cuse xlink:href='%23a' transform='rotate(15)'/%3e%3c/g%3e%3cuse xlink:href='%23b' transform='rotate(30)'/%3e%3c/g%3e%3cuse xlink:href='%23c' transform='rotate(60)'/%3e%3c/g%3e%3cuse xlink:href='%23d' transform='rotate(120)'/%3e%3cuse xlink:href='%23d' transform='rotate(-120)'/%3e%3c/g%3e%3c/svg%3e)
