Safety and efficacy of the addition of simvastatin to cetuximab in previously treated KRAS mutant metastatic colorectal cancer patients.

INTRODUCTION: Cetuximab is registered for use in colorectal cancer (CRC) patients with RAS wild-type tumours only. Simvastatin blocks the mevalonate pathway and thereby interferes with the post-translational modification (prenylation) of KRAS. We hypothesize that the activated KRAS pathway in KRAS mutant tumors can be inhibited by simvastatin rendering these tumors sensitive to the EGFR inhibitor cetuximab. METHODS: A Simon two-stage, single-arm, phase II study was performed to test the efficacy and safety of the addition of simvastatin to cetuximab in patients with a KRAS mutation in their CRC tumour who were previously treated with fluoropyrimidine, oxaliplatin and irinotecan based regimens. The primary endpoint was to test the percentage of patients alive and free from progression 12.5 weeks after the first administration of cetuximab. Our hypothesis was that at least 40% was free from progression, comparable to, though slightly lower than in KRAS wild-type patients. RESULTS: Four of 18 included patients (22.2%) were free from progression at the primary endpoint time. The time to progression in these 4 patients ranged from 20.3 to 47 weeks. CONCLUSION: Based on the current study we conclude that the theoretical concept of KRAS modulation with simvastatin was not applicable in the clinic, as we were not able to restore sensitivity to cetuximab in CRC patients harbouring a somatic KRAS mutation.

Pharmacokinetics and safety of panitumumab in a patient with chronic kidney disease.

PURPOSE: Data on panitumumab dosing in cancer patients with renal insufficiency are lacking. Here, we report a 63-year-old metastatic colorectal cancer patient with chronic kidney injury with a glomerular filtration rate of approximately 11 mL/min. METHODS: Pharmacokinetic parameters, including dose-normalized area under the curve, clearance and elimination half-life (T 1/2) after the 11th and 12th infusions were estimated using trapezoidal non-compartmental methods. Data were compared to previous reported pharmacokinetic data from studies in patients with normal renal function. RESULTS: The results show that the pharmacokinetic data in this patient with kidney failure are comparable to those in patients with adequate renal function. Moreover the treatment was well tolerated in this patient. CONCLUSION: This study suggests that panitumumab can be safely used in cancer patients with renal impairment without dose adjustment.

Pharmacokinetics of panitumumab in a patient with liver dysfunction: a case report.

PURPOSE: Panitumumab is used for the treatment for metastatic RAS wild-type colorectal cancer (mCRC). It is likely that many of these patients will present with liver metastases and some with liver dysfunction. The pharmacokinetics in patients with hepatic impairment has not been investigated, and dosage adjustments are undetermined. Here, we present a case of a patient with progressive mCRC and liver dysfunction. METHODS: A heavily pretreated KRAS wild-type mCRC patient with liver disease Child-Pugh class B was treated with 2-weekly intravenous panitumumab (6 mg/kg). The patient received 2 doses of 490 mg i.v. panitumumab after which progressive disease was documented. Toxicities were graded using CTCAEv4.0. Serum samples were collected, and panitumumab concentrations were determined using a validated immunoassay. Pharmacokinetic parameters after the first dose, including dose-normalized AUC from time zero-day 14, clearance (CL), and elimination half-life (T1/2), were estimated via trapezoidal noncompartmental methods. Data were compared to historical data from a population with adequate liver function, as reported by Stephenson (Clin Colorectal Cancer, 8:29-37, 2009). Values within the range of the mean ±1 standard deviation (SD) were considered not deviant. RESULTS: Calculated AUC after the first dose of 6 mg/kg panitumumab in this patient with hepatic dysfunction was 877 µg day/mL (Stephenson's cohort 1: 744 ± 195 µg day/mL). Estimated T1/2 was 3.58 days (5.28 ± 1.90 days), and CL was 6.9 mL/day/kg (8.21 ± 3.79 mL/day/kg). Estimated PK parameters during the first cycle were inside reported mean ±1 SD of historical controls without liver dysfunction. No toxicity was reported during treatment; particularly, no diarrhea and skin toxicity were noticed. CONCLUSIONS: The pharmacokinetics of panitumumab in this patient suffering from metastatic colorectal cancer with liver dysfunction Child-Pugh class B was similar compared to patients with adequate liver function. Moreover, no substantial toxicity was detected. The here-presented data may help clinical decision making in real-life practice. Two-weekly panitumumab monotherapy seems to be safely applicable in patients with KRAS wild-type mCRC and hepatic dysfunction, without the need for any dose adjustments.

Pharmacokinetics and safety of cetuximab in a patient with renal dysfunction.

INTRODUCTION: In the literature, data on the effect of renal impairment on the pharmacokinetics of anticancer drugs are scarce. Here, we report a 68-year-old metastatic osteosarcoma patient with impaired renal function due to prior chemotherapy, who was treated on compassionate use basis with 400 mg/m(2) cetuximab. MATERIAL AND METHODS: Pharmacokinetic parameters after the first dose, including dose-normalised AUC from time zero to day 7, clearance, elimination half-life (t(1/2)), were estimated using trapezoidal non-compartmental methods and compared to pharmacokinetic data from a study population with normal kidney function. RESULTS: The results showed that the pharmacokinetics of cetuximab in this patient with renal failure was similar to that with adequate renal function. CONCLUSION: This study suggests that cetuximab can be safely used in cancer patients with renal impairment without dose adjustment.

Recommendations on management of EGFR inhibitor-induced skin toxicity: a systematic review.

Epidermal growth factor receptor (EGFR) inhibitors, such as the monoclonal antibodies cetuximab and panitumumab, have proven efficacy in various types of cancer. However, these agents frequently result in skin toxicity, due to the expression of the EGFR in the skin. A correlation between the occurrence of skin toxicity and anti-tumor activity has been suggested in several phase III studies. However, since skin toxicity may impair the quality of life, and severe skin toxicity requires dose reduction or interruption, adequate and timely management of skin toxicity is important to maximize the anti-tumor efficacy of the EGFR inhibitor, as well as maintaining the patient's quality of life. Due to the small number of randomized controlled trials conducted in the field of EGFR inhibitor-induced skin toxicity so far, it is not possible yet to generate evidence based guidelines on its management. Here, we review and discuss available trials and case studies reporting on the management of EGFR inhibitor-induced skin toxicity.