Open-Label Phase III Trial of Panitumumab Plus Best Supportive Care Compared With Best Supportive Care Alone in Patients With Chemotherapy-Refractory Metastatic Colorectal Cancer

Cutsem, Éric Van; Peeters, Marc; Siena, Salvatore; Humblet, Yves; Hendlisz, Alain; Neyns, Bart; Canon, Jean-Luc; Laethem, Jean‐Luc Van; Maurel, Joan; Richardson, Gary; Wolf, Michael; Amado, Rafael G.

doi:10.1200/jco.2006.08.1620

Cited by 1,793 publications

(1,226 citation statements)

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“…Jonker et al (2007) have evaluated, in a phase III clinical study, the role of cetuximab in patients with mCRC pretreated with an oxaliplatin-and irinotecan-based chemotherapy, showing an improvement in terms of OS of cetuximab plus best supportive care (BSC) respect to BSC alone (median OS of 6.1 vs 4.6 months, P ¼ 0.0046). Van Cutsem et al (2007) in a similar setting of patients have compared panitumumab plus BSC to BSC alone, showing that panitumumab prolonged the PFS (HR: 0.54; 95% CI: 0.44 -0.66, Po0.0001), with no difference in terms of OS. Despite the promising results, some issues could limit the use of these therapies in this setting of patients, such as the low impact on survival, the high cost of the drugs and the significant higher rate of grade 3 -4 adverse events with respect to BSC.…”

Section: Discussionmentioning

confidence: 99%

A pharmacokinetic and pharmacodynamic study on metronomic irinotecan in metastatic colorectal cancer patients

et al. 2008

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The pharmacokinetics (PK) and pharmacodynamics (PD) of metronomic irinotecan have not been studied in cancer patients. The aim of the study is to investigate the PK/PD profile of irinotecan/SN-38 administered by metronomic schedule. Twenty chemotherapyrefractory or chemotherapy-resistant patients with metastatic colorectal carcinoma were enrolled. Irinotecan was infused continuously as follows: irinotecan 1.4 mg m À2 day À1 (n ¼ 7), 2.8 mg m À2 day À1 (n ¼ 5) and 4.2 mg m À2 day À1 (n ¼ 8). Drug levels were examined by HPLC, whereas ELISAs and real-time RT-PCR were used, respectively, for the measurement of plasma levels and gene expression in peripheral blood mononuclear cells of vascular endothelial growth factor/thrombospondin-1. Pharmacokinetic analysis demonstrated that the steady-state levels (C ss ) of SN-38 were between 1 and 3.3 ng ml À1 . From a PD point of view, higher thrombospondin-1 (TSP-1) plasma levels (153.4±30.1 and 130.4±9.2% at day 49 vs pretreatment values at 1.4 and 2.8 mg m À2 day À1 dose levels, respectively) and increased gene expression in PBMC were found during the metronomic irinotecan infusion, especially at the lower doses. Four patients (20%) obtained a stable disease (median 3.9 months) despite progressing during previous standard irinotecan schedule. Toxicities 4grade 1 were not observed. Metronomic irinotecan administration is very well tolerated and induces an increase of gene expression and plasma concentration of TSP-1 at low plasma SN-38 concentrations.

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Section: Discussionmentioning

confidence: 99%

A pharmacokinetic and pharmacodynamic study on metronomic irinotecan in metastatic colorectal cancer patients

et al. 2008

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Section: Introductionmentioning

confidence: 99%

“…[1][2][3][4] However, resistance to cetuximab is common, and only 10% to 20% of patients truly benefit from the treatment. 4,5 Recently, it has been widely demonstrated that mutations in v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) codons 12 and 13 are major predictive biomarkers for resistance to cetuximab treatment. [6][7][8][9] With reference to these findings, the European Medicines Agency 10 and, subsequently, the US Food and Drug Administration 11 have suggested that patients who have mCRC with KRAS codon 12 and codon 13 mutations should be excluded from cetuximab treatment.…”

Section: Introductionmentioning

confidence: 99%

KRAS p.G13D mutation and codon 12 mutations are not created equal in predicting clinical outcomes of cetuximab in metastatic colorectal cancer

Chen

Huang

Yang

et al. 2012

Cancer

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BACKGROUND:The authors conducted a systematic review and meta-analysis to examine whether patients who had metastatic colorectal cancer (mCRC) with the v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) p.G13D mutation (an amino acid substitution at position 13 in KRAS from a glycine to an aspartic acid) and received cetuximab treatment had better clinical outcomes than patients who had mCRC tumors with KRAS codon 12 mutations. METHODS: Relevant studies were identified by a search of MEDLINE, EMBASE, the Chinese Biomedical Database, and Wan Fang Digital Journals from inception to October 2011. The primary clinical outcomes included the objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). The pooled relative risk (RR) or hazard ratio (HR) was estimated by using fixed-effects or random-effects models according to heterogeneity between studies. RESULTS: Ten studies were considered eligible that included 1487 patients with mCRC. Patients who had tumors with the KRAS p.G13D mutation had a significantly higher ORR (10 studies; RR, 1.642; 95% confidence interval [CI], 1.131-2.384), longer PFS (1 study; HR, 0.54; 95% CI, 0.36-0.81), and longer OS (1 study; HR, 0.52; 95% CI, 0.33-0.80) than patients who had tumors with KRAS codon 12 mutations. Compared with patients who had KRAS wild-type tumors, patients with the p.G13D mutation had a significantly lower ORR (9 studies; RR, 0.540; 95% CI, 0.381-0.765) and nonsignificantly shorter PFS (1 study; HR, 0.99; 95% CI, 0.68-1.45) and OS (1 study; HR, 1.01; 95% CI, 0.66-1.54). CONCLUSIONS: Patients who had mCRC with the KRAS p.G13D mutation appeared to benefit more from cetuximab than patients who had tumors with KRAS codon 12 mutations. However, because of the limited sample sizes in the current meta-analysis, these results should be interpreted with caution. Cancer 2013;119:714-21.

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“…Blue spheroids exemplify factors/processes that are integral components of the corresponding feature and which are currently being targeted for cancer therapy; numbers refer to the following publications: (1) Tennant et al, 2010;(2) Desgrosellier and Cheresh, 2010;(3) Lessene et al, 2008 (4) Lane and Chabner, 2009;(5) Bianco et al, 2007;(6) Granchi et al, 2010;(7) Ferrara et al, 2004 and (8) Berdis, 2008. Novel paradigms for cancer therapy V Pavet et al phosphorylation and signaling, and thus inhibiting proliferation and promoting apoptosis. Panitumumab has been approved for the treatment of metastatic colorectal cancer showing preliminary activity in phase I/II clinical trials, and phase III clinical trials are currently ongoing (Van Cutsem et al, 2007). An interesting addition to this concept is that rexinoids exclusively exert their apoptotic action under conditions in which growth factor signaling is impaired (Shankaranarayanan et al, 2009), suggesting that the combination of both anticancer treatments might be an attractive strategy.…”

Section: Current Therapeutic Paradigms To Treat Cancermentioning

confidence: 99%

Towards novel paradigms for cancer therapy

et al. 2010

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Cancer is a complex progressive multistep disorder that results from the accumulation of genetic and epigenetic abnormalities, which lead to the transformation of normal cells into malignant derivatives. Despite enormous progress in the understanding of cancer biology including the decryption of multiple regulatory networks governing cell growth and death, and despite the possibility of analyzing (epi)genetic deregulation at the genome-wide scale, cancertargeted therapy is still the exception. In fact, to date there are still far too few examples of therapies leading to cure; treatment-derived toxicity is a major issue, and cancer remains to be one of the largest causes of death worldwide. The purpose of this review is to discuss the state of the art of cancer therapy with respect to the key issue of any treatment, namely its target selectivity. Therefore, we recapitulate and discuss current concepts and therapies targeting tumorspecific features, including oncofusion proteins, aberrant kinase activities and epigenetic tumor makeup. We analyze strategies designed to induce tumor-selective death such as the use of oncolytic virus, tumoricidal proteins (NS1, Eorf4, apoptin, HAMLET (human a-lactalbumin made lethal to tumor cells)) and activation of signaling pathways involved in tumor surveillance. We emphasize the potential of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) pathway, an essential component of the evolutionary developed defense systems that eradicate malignant cells. Finally, we discuss the necessity of targeting tumor-initiating cells (TICs) to avoid relapse and increase the chances of complete remission, and describe emerging concepts that might provide novel avenues for cancer therapy.

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Open-Label Phase III Trial of Panitumumab Plus Best Supportive Care Compared With Best Supportive Care Alone in Patients With Chemotherapy-Refractory Metastatic Colorectal Cancer

Abstract: Panitumumab significantly improved PFS with manageable toxicity in patients with chemorefractory colorectal cancer.

Cited by 1,793 publications

References 29 publications

A pharmacokinetic and pharmacodynamic study on metronomic irinotecan in metastatic colorectal cancer patients

A pharmacokinetic and pharmacodynamic study on metronomic irinotecan in metastatic colorectal cancer patients

KRAS p.G13D mutation and codon 12 mutations are not created equal in predicting clinical outcomes of cetuximab in metastatic colorectal cancer

Towards novel paradigms for cancer therapy

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