TY - JOUR
T1 - Phase II trial of temsirolimus alone and in combination with irinotecan for KRAS mutant metastatic colorectal cancer
T2 - Outcome and results of KRAS mutational analysis in plasma
AU - Spindler, Karen-Lise Garm
AU - Sørensen, Morten
AU - Pallisgaard, Niels
AU - Andersen, Rikke
AU - Havelund, Birgitte Mayland
AU - Ploen, John
AU - Lassen, Ulrik
AU - Jakobsen, Leif Anders
PY - 2013/6
Y1 - 2013/6
N2 - Background. Patients with chemotherapy refractory metastatic colorectal cancer and KRAS mutations have no effective treatment option. The present study evaluated the efficacy of temsirolimus in chemotherapy refractory mCRC with KRAS mutations. Furthermore, we wanted to investigate if resistance to temsirolimus could be reversed by the addition of irinotecan. Finally, we analyzed pre-treatment blood samples for KRAS mutations to investigate the association between quantitative measures of KRAS mutated alleles and clinical outcome. Material and methods. Patients received weekly temsirolimus 25 mg until progression. Thereafter patients were treated with combination therapy comprising biweekly irinotecan 180 mg/m and weekly temsirolimus. A polymerase chain reaction method was used to quantify the KRAS mutated alleles in plasma (pKRAS). Results. Sixty-four patients were included. Treatment was well tolerated. Thirty-eight percent achieved stable disease on monotherapy and 63% on combination therapy. Four and eight patients had a minimal response, respectively. Median overall survival was 160 days. Median time to progression was 45 and 84 days, respectively. The concordance between KRAS status in tumor and plasma was 82%. All patients with tumor reduction had low levels of pKRAS. Patients with high pKRAS had a 77% risk of early progression on monotherapy compared to 43% in patients with lower levels. Multivariate survival analysis confirmed that pKRAS was a strong prognostic factor. Conclusion. Temsirolimus has limited efficacy in chemotherapy resistant KRAS mutant disease, but plasma KRAS quantification is a strong predictor of outcome.
AB - Background. Patients with chemotherapy refractory metastatic colorectal cancer and KRAS mutations have no effective treatment option. The present study evaluated the efficacy of temsirolimus in chemotherapy refractory mCRC with KRAS mutations. Furthermore, we wanted to investigate if resistance to temsirolimus could be reversed by the addition of irinotecan. Finally, we analyzed pre-treatment blood samples for KRAS mutations to investigate the association between quantitative measures of KRAS mutated alleles and clinical outcome. Material and methods. Patients received weekly temsirolimus 25 mg until progression. Thereafter patients were treated with combination therapy comprising biweekly irinotecan 180 mg/m and weekly temsirolimus. A polymerase chain reaction method was used to quantify the KRAS mutated alleles in plasma (pKRAS). Results. Sixty-four patients were included. Treatment was well tolerated. Thirty-eight percent achieved stable disease on monotherapy and 63% on combination therapy. Four and eight patients had a minimal response, respectively. Median overall survival was 160 days. Median time to progression was 45 and 84 days, respectively. The concordance between KRAS status in tumor and plasma was 82%. All patients with tumor reduction had low levels of pKRAS. Patients with high pKRAS had a 77% risk of early progression on monotherapy compared to 43% in patients with lower levels. Multivariate survival analysis confirmed that pKRAS was a strong prognostic factor. Conclusion. Temsirolimus has limited efficacy in chemotherapy resistant KRAS mutant disease, but plasma KRAS quantification is a strong predictor of outcome.
U2 - 10.3109/0284186x.2013.776175
DO - 10.3109/0284186x.2013.776175
M3 - Journal article
C2 - 23514584
SN - 0284-186X
VL - 52
SP - 963
EP - 970
JO - Acta Oncologica
JF - Acta Oncologica
IS - 5
ER -
